Leflunomida

Leflunomida is indicated for the treatment of adult patients with:

- active rheumatoid arthritis as a "disease-modifying antirheumatic drug" (DMARD),

Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may result in an increased risk of serious adverse reactions; therefore, the initiation of Leflunomida treatment has to be carefully considered regarding these benefit/risk aspects.

Moreover, switching from Leflunomida to another DMARD without following the washout procedure may also increase the risk of serious adverse reactions even for a long time after the switching.

The treatment should be initiated and supervised by specialists experienced in the treatment of rheumatoid arthritis.

Alanine aminotransferase (ALT) or serum glutamopyruvate transferase (SGPT) and a complete blood cell count, including a differential white blood cell count and a platelet count, must be checked simultaneously and with the same frequency:

- before initiation of Leflunomida,

- every two weeks during the first six months of treatment, and

- every 8 weeks thereafter.

Posology

In rheumatoid arthritis: Leflunomida therapy is usually started with a loading dose of 100 mg once daily for 3 days.

- Omission of the loading dose may decrease the risk of adverse events. The recommended maintenance dose is Leflunomida 10 mg to 20 mg once daily depending on the severity (activity) of the disease.

The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months.

There is no dose adjustment recommended in patients with mild renal insufficiency.

No dosage adjustment is required in patients above 65 years of age.

Paediatric population

Leflunomida is not recommended for use in patients below 18 years since efficacy and safety in juvenile rheumatoid arthritis (JRA) have not been established.

Method of Administration

Leflunomida film-coated tablets should be swallowed whole with sufficient amounts of liquid. The extent of Leflunomida absorption is not affected if it is taken with food.

- Patients with impairment of liver function,

- Patients with severe immunodeficiency states, e.g. AIDS,

- Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid arthritis,

- Patients with serious infections ,

- Patients with moderate to severe renal insufficiency, because insufficient clinical experience is available in this patient group,

- Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome,

- Pregnant women, or women of childbearing potential who are not using reliable contraception during treatment with Leflunomida and thereafter as long as the plasma levels of the active metabolite are above 0.02 mg/l. Pregnancy must be excluded before start of treatment with Leflunomida,

- Breast-feeding women.

Interference with determination of ionised calcium levels

The measurement of ionised calcium levels might show falsely decreased values under treatment with Leflunomida and/or teriflunomide (the active metabolite of Leflunomida) depending on the type of ionised calcium analyser used (e.g. blood gas analyser). Therefore, the plausibility of observed decreased ionised calcium levels needs to be questioned in patients under treatment with Leflunomida or teriflunomide. In case of doubtful measurements, it is recommended to determine the total albumin adjusted serum calcium concentration.

Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not advisable.

The active metabolite of Leflunomida, A771726, has a long half-life, usually 1 to 4 weeks. Serious undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below), even if the treatment with Leflunomida has been stopped. Therefore, when such toxicities occur or if for any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has to be followed. The procedure may be repeated as clinically necessary.

Colitis, including microscopic colitis has been reported in patients treated with Leflunomida. In patients on Leflunomida treatment presenting unexplained chronic diarrhoea appropriate diagnostic procedures should be performed.

Liver reactions

Rare cases of severe liver injury, including cases with fatal outcome, have been reported during treatment with Leflunomida. Most of the cases occurred within the first 6 months of treatment. Co-treatment with other hepatotoxic medicinal products was frequently present. It is considered essential that monitoring recommendations are strictly adhered to.

ALT (SGPT) must be checked before initiation of Leflunomida and at the same frequency as the complete blood cell count (every two weeks) during the first six months of treatment and every 8 weeks thereafter.

For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, dose reduction from 20 mg to 10 mg may be considered and monitoring must be performed weekly. If ALT (SGPT) elevations of more than 2-fold the upper limit of normal persist or if ALT elevations of more than 3-fold the upper limit of normal are present, Leflunomida must be discontinued and wash-out procedures initiated. It is recommended that monitoring of liver enzymes be maintained after discontinuation of Leflunomida treatment, until liver enzyme levels have normalised.

Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with Leflunomida.

Since the active metabolite of Leflunomida, A771726, is highly protein bound and cleared via hepatic metabolism and biliary secretion, plasma levels of A771726 are expected to be increased in patients with hypoproteinaemia. Leflunomida is contraindicated in patients with severe hypoproteinaemia or impairment of liver function.

Haematological reactions

Together with ALT, a complete blood cell count, including differential white blood cell count and platelets, must be performed before start of Leflunomida treatment as well as every 2 weeks for the first 6 months of treatment and every 8 weeks thereafter.

In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological disorders is increased. If such effects occur, a washout (see below) to reduce plasma levels of A771726 should be considered.

In case of severe haematological reactions, including pancytopenia, Leflunomida and any concomitant myelosuppressive treatment must be discontinued and a Leflunomida washout procedure initiated.

Combinations with other treatments

The use of Leflunomida with antimalarials used in rheumatic diseases (e.g. chloroquine and hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other immunosuppressive agents including Tumour Necrosis Factor alpha-Inhibitors has not been adequately studied up to now in randomised trials. The risk associated with combination therapy, in particular in long-term treatment, is unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or haematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.

Co-administration of teriflunomide with Leflunomida is not recommended, as Leflunomida is the parent compound of teriflunomide.

Switching to other treatments

As Leflunomida has a long persistence in the body, a switching to another DMARD (e.g. methotrexate) without performing the washout procedure (see below) may raise the possibility of additive risks even for a long time after the switching (i.e. kinetic interaction, organ toxicity).

Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate) may result in increased side effects; therefore, the initiation of Leflunomida treatment has to carefully be considered regarding these benefit/risk aspects and closer monitoring is recommended in the initial phase after switching.

Skin reactions

In case of ulcerative stomatitis, Leflunomida administration should be discontinued.

Very rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported in patients treated with Leflunomida. As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, Leflunomida and any other possibly associated treatment must be discontinued, and a Leflunomida washout procedure initiated immediately. A complete washout is essential in such cases. In such cases re-exposure to Leflunomida is contraindicated.

Pustular psoriasis and worsening of psoriasis have been reported after the use of Leflunomida. Treatment withdrawal may be considered taking into account patient's disease and past history.

Infections

It is known that medicinal products with immunosuppressive properties - like Leflunomida - may cause patients to be more susceptible to infections, including opportunistic infections. Infections may be more severe in nature and may, therefore, require early and vigorous treatment. In the event that severe, uncontrolled infections occur, it may be necessary to interrupt Leflunomida treatment and administer a washout procedure as described below.

Rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients receiving Leflunomida among other immunosuppressants.

Before starting treatment, all patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. This can include medical history, possible previous contact with tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-gamma release assay, as applicable. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised. Patients with a history of tuberculosis should be carefully monitored because of the possibility of reactivation of the infection.

Respiratory reactions

Interstitial lung disease, as well as rare cases of pulmonary hypertension, have been reported during treatment with Leflunomida. The risk of their occurrence can be increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy. Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate.

Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving Leflunomida. Most patients improved after discontinuation of Leflunomida. However there was a wide variability in final outcome, i.e. in some patients the neuropathy resolved and some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking Leflunomida develops a peripheral neuropathy, consider discontinuing Leflunomida therapy and performing the drug elimination procedure.

Blood pressure

Blood pressure must be checked before the start of Leflunomida treatment and periodically thereafter.

Procreation (recommendations for men)

Male patients should be aware of the possible male-mediated foetal toxicity. Reliable contraception during treatment with Leflunomida should also be guaranteed.

There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to father a child should consider discontinuing use of Leflunomida and taking colestyramine 8 g 3 times daily for 11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.

In either case the A771726 plasma concentration is then measured for the first time. Thereafter, the A771726 plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/l, and after a waiting period of at least 3 months, the risk of foetal toxicity is very low.

Washout procedure

Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal is administered 4 times daily. Duration of a complete washout is usually 11 days. The duration may be modified depending on clinical or laboratory variables.

Lactose

Leflunomida contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

In the case of side effects such as dizziness the patient's ability to concentrate and to react properly may be impaired. In such cases patients should refrain from driving cars and using machines.

Summary of the safety profile

The most frequently reported adverse effects with Leflunomida are: mild increase in blood pressure, leucopenia, paraesthesia, headache, dizziness, diarrhoea, nausea, vomiting, oral mucosal disorders (e.g. aphthous stomatitis, mouth ulceration), abdominal pain, increased hair loss, eczema, rash (including maculo-papular rash), pruritus, dry skin, tenosynovitis, CPK increased, anorexia, weight loss (usually insignificant), asthenia, mild allergic reactions and elevation of liver parameters (transaminases (especially ALT), less often gamma-GT, alkaline phosphatase, bilirubin).

Classification of expected frequencies:

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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard.

Symptoms

There have been reports of chronic overdose in patients taking Leflunomida at daily doses up to five times the recommended daily dose, and reports of acute overdose in adults and children. There were no adverse events reported in the majority of case reports of overdose. Adverse events consistent with the safety profile for Leflunomida were: abdominal pain, nausea, diarrhoea, elevated liver enzymes, anaemia, leucopenia, pruritus and rash.

Management

In the event of an overdose or toxicity, colestyramine or charcoal is recommended to accelerate elimination. Colestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49% to 65% in 48 hours.

Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite A771726 by 37% in 24 hours and by 48% in 48 hours. These washout procedures may be repeated if clinically necessary.

Studies with both haemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the primary metabolite of Leflunomida, is not dialysable

Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA13.

Human pharmacology

Leflunomida is a disease-modifying anti-rheumatic agent with antiproliferative properties.

Animal pharmacology

Leflunomida is effective in animal models of arthritis and of other autoimmune diseases and transplantation, mainly if administered during the sensitisation phase. It has immunomodulating/ immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory properties. Leflunomida exhibits the best protective effects on animal models of autoimmune diseases when administered in the early phase of the disease progression.

In vivo, it is rapidly and almost completely metabolised to A771726 which is active in vitro, and is presumed to be responsible for the therapeutic effect.

Mechanism of action

A771726, the active metabolite of Leflunomida, inhibits the human enzyme dihydroorotate dehydrogenase (DHODH) and exhibits antiproliferative activity.

Clinical efficacy and safety

Rheumatoid arthritis

The efficacy of Leflunomida in the treatment of rheumatoid arthritis was demonstrated in 4 controlled trials (1 in phase II and 3 in phase III). The phase II trial, study YU203, randomised 402 subjects with active rheumatoid arthritis to placebo (n=102), Leflunomida 5 mg (n=95), 10 mg (n=101) or 25 mg/day (n=104). The treatment duration was 6 months.

All Leflunomida patients in the phase III trials used an initial dose of 100 mg for 3 days.

Study MN301 randomised 358 subjects with active rheumatoid arthritis to Leflunomida 20 mg/day (n=133), sulphasalazine 2 g/day (n=133), or placebo (n=92). Treatment duration was 6 months.

Study MN303 was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of Leflunomida and sulphasalazine.

Study MN302 randomised 999 subjects with active rheumatoid arthritis to Leflunomida 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was optional and only used in 10% of patients. Treatment duration was 12-months.

Study US301 randomised 482 subjects with active rheumatoid arthritis to Leflunomida 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg bid. Treatment duration was 12 months.

Leflunomida at a daily dose of at least 10 mg (10 to 25 mg in study YU203, 20 mg in studies MN301 and US301) was statistically significantly superior to placebo in reducing the signs and symptoms of rheumatoid arthritis in all 3 placebo-controlled trials. The ACR (American College of Rheumatology) response rates in study YU203 were 27.7% for placebo, 31.9% for 5 mg, 50.5% for 10 mg and 54.5% for 25 mg/day. In the phase III trials, the ACR response rates for Leflunomida 20 mg/day vs. placebo were 54.6% vs. 28.6% (study MN301), and 49.4% vs. 26.3% (study US301). After 12 months with active treatment, the ACR response rates in Leflunomida patients were 52.3% (studies MN301/303), 50.5% (study MN302) and 49.4% (study US301), compared to 53.8% (studies MN301/303) in sulphasalazine patients, 64.8% (study MN302), and 43.9% (study US301) in methotrexate patients. In study MN302 Leflunomida was significantly less effective than methotrexate. However, in study US301 no significant differences were observed between Leflunomida and methotrexate in the primary efficacy parameters. No difference was observed between Leflunomida and sulphasalazine (study MN301). The Leflunomida treatment effect was evident by 1 month, stabilised by 3 to 6 months and continued throughout the course of treatment.

A randomised, double-blind, parallel-group non-inferiority study compared the relative efficacy of two different daily maintenance doses of Leflunomida, 10 mg and 20 mg. From the results it can be concluded that efficacy results of the 20 mg maintenance dose were more favourable, on the other hand, the safety results favoured the 10 mg daily maintenance dose.

Paediatric population

Leflunomida was studied in a single multicenter, randomized, double-blind, active-controlled trial in 94 patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis. Patients were 3-17 years of age with active polyarticular course JRA regardless of onset type and naive to methotrexate or Leflunomida. In this trial, the loading dose and maintenance dose of Leflunomida was based on three weight categories: <20kg, 20-40 kg, and >40kg. After 16 weeks treatment, the difference in response rates was statistically significant in favour of methotrexate for the JRA Definition of Improvement (DOI) >30 % (p=0.02). In responders, this response was maintained during 48 weeks..

The pattern of adverse events of Leflunomida and methotrexate seems to be similar, but the dose used in lighter subjects resulted in a relatively low exposure. These data do not allow an effective and safe dose recommendation.

Postmarketing Studies

A randomised study assessed the clinical efficacy response rate in DMARD-naïve patients (n=121) with early RA, who received either 20 mg or 100 mg of Leflunomida in two parallel groups during the initial three day double blind period. The initial period was followed by an open label maintenance period of three months, during which both groups received Leflunomida 20 mg daily. No incremental overall benefit was observed in the studied population with the use of a loading dose regimen. The safety data obtained from both treatment groups were consistent with the known safety profile of Leflunomida, however, the incidence of gastrointestinal adverse events and of elevated liver enzymes tended to be higher in the patients receiving the loading dose of 100 mg Leflunomida.

Leflunomida is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring opening) in gut wall and liver. In a study with radiolabelled 14C-Leflunomida in three healthy volunteers, no unchanged Leflunomida was detected in plasma, urine or faeces. In other studies, unchanged Leflunomida levels in plasma have rarely been detected, however, at ng/ml plasma levels.

The only plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for essentially all the in-vivo activity of Leflunomida.

Absorption

Excretion data from the ¹⁴C study indicated that at least about 82 to 95% of the dose is absorbed. The time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur between 1 hour and 24 hours after single administration. Leflunomida can be administered with food, since the extent of absorption is comparable in the fed and fasting state. Due to the very long half-life of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of A771726. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. In multiple dose studies in patients with rheumatoid arthritis, the pharmacokinetic parameters of A771726 were linear over the dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and to the daily dose of Leflunomida. At a dose level of 20 mg/day, average plasma concentration of A771726 at steady state is approximately 35 μg/ml. At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.

Distribution

In human plasma, A771726 is extensively bound to protein (albumin). The unbound fraction of A771726 is about 0.62%. Binding of A771726 is linear in the therapeutic concentration range. Binding of A771726 appeared slightly reduced and more variable in plasma from patients with rheumatoid arthritis or chronic renal insufficiency. The extensive protein binding of A771726 could lead to displacement of other highly-bound drugs. In vitro plasma protein binding interaction studies with warfarin at clinically relevant concentrations, however, showed no interaction. Similar studies showed that ibuprofen and diclofenac did not displace A771726, whereas the unbound fraction of A771726 is increased 2- to 3-fold in the presence of tolbutamide. A771726 displaced ibuprofen, diclofenac and tolbutamide but the unbound fraction of these drugs is only increased by 10% to 50%. There is no indication that these effects are of clinical relevance. Consistent with extensive protein binding A771726 has a low apparent volume of distribution (approximately 11 litres). There is no preferential uptake in erythrocytes.

Biotransformation

Leflunomida is metabolised to one primary (A771726) and many minor metabolites including TFMA (4-trifluoromethylaniline). The metabolic biotransformation of Leflunomida to A771726 and subsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to occur in microsomal and cytosolic cellular fractions. Interaction studies with cimetidine (non-specific cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate that in vivo CYP enzymes are involved in the metabolism of Leflunomida only to a small extent.

Elimination

Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/hr. The elimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled dose of Leflunomida, radioactivity was equally excreted in faeces, probably by biliary elimination, and in urine. A771726 was still detectable in urine and faeces 36 days after a single administration. The principal urinary metabolites were glucuronide products derived from Leflunomida (mainly in 0 to 24 hour samples) and an oxanilic acid derivative of A771726. The principal faecal component was A771726.

It has been shown in man that administration of an oral suspension of activated powdered charcoal or colestyramine leads to a rapid and significant increase in A771726 elimination rate and decline in plasma concentrations. This is thought to be achieved by a gastrointestinal dialysis mechanism and/or by interrupting enterohepatic recycling.

Renal impairment

Leflunomida was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patients on continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects appeared to be similar to healthy volunteers. A more rapid elimination of A771726 was observed in haemodialysis subjects which was not due to extraction of drug in the dialysate.

Hepatic impairment

No data are available regarding treatment of patients with hepatic impairment. The active metabolite A771726 is extensively protein bound and cleared via hepatic metabolism and biliary secretion. These processes may be affected by hepatic dysfunction.

Paediatric population

The pharmacokinetics of A771726 following oral administration of Leflunomida have been investigated in 73 paediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that paediatric patients with body weights ≤40 kg have a reduced systemic exposure (measured by Css) of A771726 relative to adult rheumatoid arthritis patients.

Elderly

Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in younger adults.

Leflunomida, administered orally and intraperitoneally, has been studied in acute toxicity studies in mice and rats. Repeated oral administration of Leflunomida to mice for up to 3 months, to rats and dogs for up to 6 months and to monkeys for up to 1 month's duration revealed that the major target organs for toxicity were bone marrow, blood, gastrointestinal tract, skin, spleen, thymus and lymph nodes.

The main effects were anaemia, leucopenia, decreased platelet counts and panmyelopathy and reflect the basic mode of action of the compound (inhibition of DNA synthesis). In rats and dogs, Heinz bodies and/or Howell-Jolly bodies were found. Other effects found on heart, liver, cornea and respiratory tract could be explained as infections due to immunosuppression. Toxicity in animals was found at doses equivalent to human therapeutic doses.

Leflunomida was not mutagenic. However, the minor metabolite TFMA (4-trifluoromethylaniline) caused clastogenicity and point mutations in vitro, whilst insufficient information was available on its potential to exert this effect in vivo.

In a carcinogenicity study in rats, Leflunomida did not show carcinogenic potential. In a carcinogenicity study in mice an increased incidence of malignant lymphoma occurred in males of the highest dose group, considered to be due to the immunosuppressive activity of Leflunomida. In female mice an increased incidence, dose-dependent, of bronchiolo-alveolar adenomas and carcinomas of the lung was noted. The relevance of the findings in mice relative to the clinical use of Leflunomida is uncertain.

Leflunomida was not antigenic in animal models.

Leflunomida was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range and exerted adverse effects on male reproductive organs in repeated dose toxicity studies. Fertility was not reduced.

Not applicable.

No special requirements for disposal.

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