Lemtrada Special Precautions

LEMTRADA is not recommended for patients with inactive disease or those stable on current therapy.
Patients treated with LEMTRADA must be given the Package Leaflet, the Patient Alert Card and the Patient Guide. Before treatment, patients must be informed about the risks and benefits, and the need to commit to follow-up from treatment initiation until at least 48-months after the last infusion of the second LEMTRADA treatment course. If an additional course is administered, safety-follow up should be continued until at least 48 months after the last infusion.
Traceability: In order to improve the traceability of biological medicinal products, the name and tha batch of the administered product should be clearly recorded.
Autoimmunity: Treatment may result in the formation of autoantibodies and increase the risk of autoimmune mediated conditions which may be serious and life threatening. Reported autoimmune conditions, include thyroid disorders, immune thrombocytopenic purpura (ITP), nephropathies (e.g. anti-glomerular basement membrane disease), autoimmune hepatitis (AIH), and acquired haemophilia A. In the post-marketing setting, patients developing multiple autoimmune disorders after LEMTRADA treatment have been observed. Patients who develop autoimmunity should be assessed for other autoimmune mediated conditions (see Contraindications). Patients and physicians should be made aware of the potential later onset of autoimmune disorders after the 48 months monitoring period.
Acquired haemophilia A: Cases of acquired haemophilia A (anti-factor VIII antibodies) have been reported in both clinical trial and post-marketing setting. Patients typically present with spontaneous subcutaneous haematomas and extensive bruising although haematuria, epistaxis, gastrointestinal or other types of bleeding may occur. A coagulopathy panel including aPTT must be obtained in all patients that present with such symptoms. Educate patients on the signs and symptoms of acquired haemophilia A and to seek immediate medical attention, if any of these symptoms are observed.
Thrombotic Thrombocytopenic Purpura (TTP): Development of TTP has been reported in patients treated with LEMTRADA during post-marketing use, including a fatal case. TTP is a serious condition that requires urgent evaluation and prompt treatment, and can develop several months after last LEMTRADA infusion. TTP may be characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, fever and renal impairment.
Autoimmune Encephalitis: Cases of autoimmune encephalitis have been reported in patients treated with LEMTRADA. Autoimmune encephalitis is characterized by subacute onset (with rapid progression over months) of memory impairment, altered mental status or psychiatric symptoms, generally in combination with new onset focal neurological findings and seizures. Patients with suspected autoimmune encephalitis should have neuroimaging (MRI), EEG, lumbar puncture and serologic testing for appropriate biomakers (e.g. neural autoantibodies) to confirm diagnosis and exclude alternative etiologies.
Immune Thrombocytopenic Purpura (ITP): Serious events of ITP have been observed in 12 (1%) patients treated in controlled clinical trials in MS (corresponding to an annualised rate 4.7 events/1000 patient years). An additional 12 serious events of ITP has been observed through a median of 6.1 years (maximum 12 years) of follow-up (cumulative annualised rate of 2.8 events/1000 patient years). One patient developed ITP that went unrecognised prior to implementation of monthly blood monitoring requirements and died from intracerebral haemorrhage. In 79.5% of cases, ITP onset occurred within 4 years after first exposure. However, in some cases ITP developed years later. Symptoms of ITP could include (but are not limited to) easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g., epistaxis, haemoptysis), heavier than normal or irregular menstrual bleeding. Haemoptysis may also be indicative of anti-GBM disease (see as follows), and an appropriate differential diagnosis has to be undertaken. Remind the patient to remain vigilant for symptoms they may experience and to seek immediate medical help if they have any concerns.
Complete blood counts with differential should be obtained prior to initiation of treatment and at monthly intervals thereafter until at least 48 months after the last infusion. After this period of time, testing should be performed based on clinical findings suggestive of ITP. If ITP is suspected a complete blood count should be obtained immediately.
If ITP onset is confirmed, appropriate medical intervention should be promptly initiated, including immediate referral to a specialist. Data from clinical trials in MS has shown that adherence to the blood monitoring requirements and education relative to signs and symptoms of ITP has led to early detection and treatment of ITP with most cases responding to first-line medical therapy.
Nephropathies: Nephropathies, including anti-glomerular basement membrane (anti-GBM) disease, have been observed in 6 (0.4%) patients in clinical trials in MS through a median of 6.1 years (maximum 12 years) of follow-up and generally occurred within 39 months following the last administration of LEMTRADA. In clinical trials, there were 2 cases of anti-GBM disease. Both cases were serious, were identified early through clinical and laboratory monitoring, and had a positive outcome after treatment.
Clinical manifestations of nephropathy may include elevation in serum creatinine, haematuria, and/or proteinuria. While not observed in clinical trials, alveolar haemorrhage manifested as haemoptysis may occur with anti-GBM disease. Haemoptysis may also be indicative of ITP or acquired haemophilia A (see previously), and an appropriate differential diagnosis has to be undertaken. The patient should be reminded to remain vigilant for symptoms they may experience and to seek immediate medical help if they have any concerns. Anti-GBM disease may lead to renal failure requiring dialysis and/or transplantation if not treated rapidly and can be life-threatening if left untreated.
Serum creatinine levels should be obtained prior to initiation of treatment and at monthly intervals thereafter until at least 48 months after the last infusion. Urinalysis with microscopy should be obtained prior to initiation and at monthly intervals thereafter until at least 48 months after the last infusion. The observation of clinically significant changes from baseline in serum creatinine, unexplained haematuria, and/or proteinuria, should prompt further evaluation for nephropathies including immediate referral to a specialist. Early detection and treatment of nephropathies may decrease the risk of poor outcomes. After this period of time, testing should be performed based on clinical findings suggestive of nephropathies.
Thyroid disorders: Thyroid endocrine disorders including autoimmune thyroid disorders have been observed in 36.8% of patients treated with LEMTRADA 12 mg in clinical trials in MS with a median of 6.1 years (maximum 12 years) of follow-up from the first LEMTRADA exposure. The incidence of thyroid events was higher in patients with a medical history of thyroid disorders both in the LEMTRADA and interferon beta 1a (IFNB-1a) treatment groups. Observed autoimmune thyroid disorders included hyperthyroidism or hypothyroidism. Most events were mild to moderate in severity. Serious endocrine events occurred in 4.4% of patients, with Basedow's disease (also known as Graves' disease), hyperthyroidism, hypothyroidism autoimmune thyroiditis, and goitre occurring in more than 1 patient. Most thyroid events were managed with conventional medical therapy however some patients required surgical intervention. In the post-marketing setting several patients who developed biopsy proven AIH had previously developed autoimmune thyroid disorders.
Thyroid function tests, such as thyroid stimulating hormone levels, should be obtained prior to initiation of treatment and every 3 months thereafter until 48 months following the last infusion. After this period of time testing should be performed based on clinical findings suggestive of thyroid dysfunction or in case of pregnancy.
Thyroid disease poses special risks in women who are pregnant (see Use in Pregnancy & Lactation).
In clinical trials, 74% of patients with positive anti-thyroid peroxidase (anti-TPO) antibodies at baseline developed a thyroid event compared with 38% of patients with a baseline negative status. The vast majority (approximately 80%) of patients who presented with a thyroid event after treatment were anti-TPO antibody negative at baseline. Therefore, regardless of pretreatment anti-TPO antibody status patients may develop a thyroid adverse reaction and must have all tests periodically performed as described previously.
Cytopenias: Suspected autoimmune cytopenias such as neutropenia, haemolytic anaemia and pancytopenia have been infrequently reported in clinical trials in MS. Complete blood count results (see ITP as previously mentioned) should be used to monitor for cytopenias, including neutropenia. If a cytopenia is confirmed, appropriate medical intervention should be promptly initiated, including referral to a specialist.
Autoimmune hepatitis and hepatic injury: Cases of autoimmune hepatitis (including fatal cases and cases requiring liver transplantation) and hepatic injury related to infections have been reported in patients treated with LEMTRADA (see Contraindications).
Liver function tests should be performed before initial treatment and at monthly intervals until at least 48 months after the last infusion. Patients should be informed about the risk of autoimmune hepatitis, hepatic injury and related symptoms.
Haemophagocytic lymphohistiocytosis (HLH): During post-marketing use, HLH (including fatal cases) has been reported in patients treated with LEMTRADA. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. HLH is characterized by fever, hepatomegaly and cytopenias. It is associated with high mortality rates if not recognized early and treated. Symptoms have been reported to occur within a few months to four years following the initiation of treatment. Patients should be informed about symptoms of HLH and time to onset. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered.
Infusion-associated Reactions (IARs): In clinical trials, infusion associated reactions (IARs) were defined as any adverse event occurring during or within 24 hours of LEMTRADA infusion. The majority of these may be due to cytokine release during infusion. Most patients treated with LEMTRADA in clinical trials in MS experienced mild to moderate IARs during and/or up to 24 hours after LEMTRADA 12 mg administration. The incidence of IARs was higher in course 1 than in subsequent courses. Through all available follow-up, including patients who received additional treatment courses, the most common IARs included headache, rash, pyrexia, nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnoea, dysgeusia, chest discomfort, generalised rash, tachycardia, bradycardia, dyspepsia, dizziness, and pain. Serious reactions occurred in 3% of patients and included cases of headache, pyrexia, urticaria, tachycardia, atrial fibrillation, nausea, chest discomfort, and hypotension. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of infusion associated reactions, but would tend to be more severe or potentially life-threatening. Reactions attributed to anaphylaxis have been reported rarely in contrast to infusion associated reactions.
It is recommended that patients be premedicated to ameliorate the effects of infusion reactions (see Dosage & Administration).
Most patients in controlled clinical trials received antihistamines and/or antipyretics before at least one LEMTRADA infusion. IARs may occur in patients despite pretreatment. Observation for infusion reactions is recommended during and for at least 2 hours after LEMTRADA infusion. Extended observation time (hospitalization) should be considered, as appropriate. If severe infusion reactions occur, the intravenous infusion should be discontinued immediately. Resources for the management of anaphylaxis or serious reactions (see as follows) should be available.
Adult Onset Still's disease (AOSD): During postmarketing use, Adult Onset Still's Disease (AOSD) has been reported in patients treated with LEMTRADA. AOSD is a rare inflammatory condition that requires urgent evaluation and treatment. Patients with AOSD may have a combination of the following signs and symptoms: fever, arthritis, rash and leukocytosis in the absence of infections, malignancies, and other rheumatic conditions. Consider interruption or discontinuation of treatment with LEMTRADA if an alternate etiology for the signs or symptoms cannot be established.
Other serious reactions temporally associated with Lemtrada infusion: During post-marketing use, rare, serious, sometimes fatal and unpredictable adverse events from various organ systems have been reported. In the majority of cases time to onset was within 1-3 days of the LEMTRADA infusion. Reactions have occurred following any of the doses and also after course number 2. Patients should be informed about the signs and symptoms and on the time to onset of the events. Patients should be advised to seek immediate medical attention if any of these symptoms occur and be informed on the potential for delayed onset.
Haemorrhagic stroke: Several of the patient reported were below 50 years of age and had no history of hypertension, bleeding disorders or concomitant anticoagulants or platelet inhibitors. In some patients there was increased blood pressure from baseline before the haemorrhage.
Myocardial ischaemia and myocardial infarction: Several of the patients reported were below 40 years of age and had no risk factors for ischemic heart disease. It was noted that in some of the patients, blood pressure and/or heart rate was temporarily abnormal during the infusion.
Dissection of the cervicocephalic arteries: Cases of cervicocephalic arterial dissections, including multiple dissections, have been reported both within the first days after the LEMTRADA infusion or later on within the first month after the infusion.
Pulmonary alveolar haemorrhage: Reported cases of temporally associated events were not related to anti-GBM disease (Goodpasteurs syndrome).
Thrombocytopenia: The reported thrombocytopenia occurred within the first days after the infusion (unlike ITP). It was often self-limiting and relatively mild, although severity and outcome was unknown in many cases.
Pericarditis: Rare cases of pericarditis, pericardial effusion and other pericardial events have been reported, both as part of acute infusion reaction and with later onset.
Pneumonitis: Pneumonitis has been reported in patients who received LEMTRADA infusions. Most cases occurred within the first month after treatment with LEMTRADA. Patients should be advised to report symptoms of pneumonitis, which may include shortness of breath, cough, wheezing, chest pain or tightness and hemoptysis.
Infusion instructions to reduce serious reactions temporally associated with LEMTRADA infusion: Pre-infusion evaluations: Obtain a baseline ECG and vital signs, including heart rate and blood pressure measurement.
Perform laboratory tests (complete blood count with differential, serum transaminases, serum creatinine, test of thyroid function and urinalysis with microscopy).
During infusion: Perform continuous/frequent (at least every hour) monitoring of heart rate, blood pressure and overall clinical status of the patients: Discontinue the infusion: In case of a severe adverse event.
If the patient shows clinical symptoms suggesting development of a serious adverse event associated with the infusion (myocardial ischemia, hemorrhagic stroke, cervico-cephalic arterial dissection or pulmonary alveolar haemorrhage).
Post-infusion: Observation for infusion reactions is recommended for a minimum of 2 hours after LEMTRADA infusion. Patients with clinical symptoms suggesting development of a serious adverse event temporally associated with the infusion (myocardial ischemia, haemorrhagic stroke, cervico-cephalic arterial dissection or pulmonary alveolar haemorrhage) should be closely monitored until complete resolution of the symptoms. The observation time should be extended (hospitalisation) as appropriate. The patients should be educated on the potential for delayed onset of infusion associated reactions and instructed to report symptoms and seek appropriate medical care.
Platelet count should be obtained immediately after infusion on Days 3 and 5 of the first infusion course, as well as immediately after infusion on Day 3 of any subsequent course. Clinically significant thrombocytopenia needs to be followed until resolution. Referral to a haematologist for management should be considered.
Infections: Infections occurred in 71% of patients treated with LEMTRADA 12 mg as compared to 53% of patients treated with subcutaneous interferon beta-1a [IFNB 1a] (44mcg 3-times weekly) in controlled clinical trials in MS up to 2 years in duration and were predominantly mild to moderate in severity. Infections that occurred more often in LEMTRADA-treated patients than IFNB 1a patients included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, oral herpes, influenza, and bronchitis. Serious infections occurred in 2.7% of patients treated with LEMTRADA as compared to 1% of patients treated with IFNB-1a in controlled clinical trials in MS. Serious infections in the LEMTRADA group included: appendicitis, gastroenteritis, pneumonia, herpes zoster, and tooth infection. Infections were generally of typical duration and resolved following conventional medical treatment.
The cumulative annualised rate of infections was 0.99 through a median of 6.1 years (maximum 12 years) of follow-up from the first LEMTRADA exposure, as compared to 1.27 in controlled clinical trials.
Serious varicella zoster virus infections, including primary varicella and varicella zoster re-activation, have occurred more often in patients treated with LEMTRADA 12 mg (0.4%) in clinical trials as compared to IFNB-1a (0%). Cervical human papilloma virus (HPV) infection, including cervical dysplasia and anogenital warts, has also been reported in patients treated with LEMTRADA 12 mg (2%). It is recommended that HPV screening be completed annually for female patients.
Cytomegalovirus infections (CMV) including cases of CMV reactivation have been reported in LEMTRADA-treated patients. Most cases occurred within 2 months of alemtuzumab dosing. Before initiation of therapy, evaluation of immune serostatus could be considered according to local guidelines.
Epstein-Barr virus (EBV) infection, including reactivation and severe and sometimes fatal EBV hepatitis cases, has been reported in LEMTRADA-treated patients.
Tuberculosis has been reported for patients treated with LEMTRADA and IFNB-1a in controlled clinical trials. Active and latent tuberculosis, including a few cases of disseminated tuberculosis, have been reported in 0.3% of the patients treated with LEMTRADA, most often in endemic regions. Before initiation of therapy, all patients must be evaluated for both active or inactive ("latent") tuberculosis infection, according to local guidelines.
Listeriosis/Listeria meningitis has been reported in LEMTRADA treated patients, generally within one month of LEMTRADA infusion. To reduce the risk of infection, patients receiving LEMTRADA should avoid ingestion of uncooked or undercooked meats, soft cheeses and unpasteurized dairy products two weeks prior to, during, and for at least one month after LEMTRADA infusion.
Superficial fungal infections, especially oral and vaginal candidiasis, occurred more commonly in LEMTRADA-treated patients (12%) than in patients treated with IFNB-1a (3%) in controlled clinical trials in MS.
Initiation of treatment with LEMTRADA should be delayed in patients with severe active infection until resolution. Patients receiving LEMTRADA should be instructed to report symptoms of infections to a physician.
Prophylaxis with an oral anti-herpes agent should be initiated starting on the first day of LEMTRADA treatment and continuing for a minimum of 1 month following each course of treatment. In clinical trials patients were administered cyclovir 200 mg twice a day or equivalent.
LEMTRADA has not been administered for treatment of MS concomitantly with or following antineoplastic or immunosuppressive therapies. As with other immunomodulating therapies, potential combined effects on the patient's immune system should be taken into account when considering administration of LEMTRADA. Concomitant use of LEMTRADA with any of these therapies could increase the risk of immunosuppression.
No data are available on the association of LEMTRADA with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) reactivation as patients with evidence of active or chronic infections were excluded from clinical trials. Screening patients at high risk of HBV and/or HCV infection before initiation of LEMTRADA should be considered and caution should be exercised in prescribing LEMTRADA to patients identified as carriers of HBV and/or HCV as these patients may be at risk of irreversible liver damage relative to a potential virus reactivation as a consequence of their pre-existing status.
Progressive Multifocal Leukoencephalopathy (PML): Rare cases of PML (including fatal), have been reported in MS patients after treatment with alemtuzumab. Patients treated with alemtuzumab must be monitored for any signs that may be suggestive of PML. Risk factors of special importance include previous immunosuppressive treatment, in particular other MS treatments with known risk of causing PML.
MRI findings may be apparent before clinical signs or symptoms. Prior to initiation and readministration of alemtuzumab treatment, MRI scan should be made and evaluated for signs that are consistent with PML. Further evaluation, including cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments should be performed as appropriate. The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their relatives or caregivers about their treatment, since they may notice symptoms that the patient is not aware of. PML should be considered as a differential diagnosis in any MS patient taking alemtuzumab presenting with neurological symptoms and/or new brain lesions in MRI.
If a diagnosis of PML has been made, treatment with alemtuzumab should not be started or restarted.
Acute acalculous cholecystitis: LEMTRADA may increase the risk of acute acalculous cholecystitis. In controlled clinical studies, 0.2% of LEMTRADA-treated MS patients developed acute acalculous cholecystitis, compared to 0% of patients treated with INFB-1a. During post-marketing use, additional cases of acute acalculous cholecystitis have been reported in LEMTRADA-treated patients. Time to onset of symptoms ranged from less than 24 hours to 2 months after LEMTRADA infusion. Most patients were treated conservatively with antibiotics and recovered without surgical intervention, whereas others underwent cholecystectomy. Symptoms of acute acalculous cholecystitis include abdominal pain, abdominal tenderness, fever, nausea, and vomiting. Acute acalculous cholecystitis is a condition that may be associated with high morbidity and mortality rates if not diagnosed early and treated. If acute acalculous cholecystitis is suspected, evaluate and treat promptly.
Malignancy: As with other immunomodulatory therapies, caution should be exercised in initiating LEMTRADA therapy in patients with pre-existing and/or an on-going malignancy. It is not currently known if LEMTRADA confers a higher risk for developing thyroid malignancies, since thyroid autoimmunity may itself be a risk factor for thyroid malignancies.
Contraception: Placental transfer and potential pharmacologic activity of LEMTRADA were observed in mice during gestation and following delivery. Women of childbearing potential should use effective contraceptive measures during treatment and for 4 months following a course of LEMTRADA treatment (see Use in Pregnancy & Lactation).
Vaccines: It is recommended that patients have completed local immunisation requirements at least 6 weeks prior to treatment with LEMTRADA. The ability to generate an immune response to any vaccine following LEMTRADA treatment has not been studied.
The safety of immunisation with live viral vaccines following a course of LEMTRADA treatment has not been formally studied in controlled clinical trials in MS and should not be administered to MS patients who have recently received a course of LEMTRADA.
Varicella zoster virus antibody testing/vaccination: As for any immune modulating medicinal product, before initiating a course of LEMTRADA treatment, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to treatment initiation with LEMTRADA. To allow for the full effect of the VZV vaccination to occur, treatment with LEMTRADA should be postponed for 6 weeks following vaccination.
Recommended laboratory tests for monitoring patients: Clinical examination and laboratory tests should be conducted at periodic intervals until at least 48 months following the last treatment course of LEMTRADA in order to monitor for early signs of autoimmune diseases: Complete blood count with differential (serum transaminases and serum creatinine levels (prior to treatment initiation and at monthly intervals thereafter).
Urinalysis with microscopy (prior to treatment initiation and at monthly intervals thereafter).
A test of thyroid function, such as thyroid stimulating hormone level (prior to treatment initiation and every 3 months thereafter).
Information from use of alemtuzumab prior to the marketing authorisation of Lemtrada outside of company-sponsored studies: The following adverse reactions were identified prior to registration of LEMTRADA during use of alemtuzumab for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL), as well as for the treatment of other disorders, generally at higher and more frequent doses (e.g. 30 mg) than that recommended in the treatment of MS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to alemtuzumab exposure.
Autoimmune disease: Autoimmune events reported in alemtuzumab-treated patients include neutropenia, haemolytic anaemia (including a fatal case), acquired haemophilia, anti-GBM disease, and thyroid disease. Serious and sometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, autoimmune thrombocytopenia, aplastic anaemia, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyradiculoneuropathy have been reported in alemtuzumab-treated non-MS patients. A positive Coombs test has been reported in an alemtuzumab-treated oncology patient. A fatal event of transfusion associated graft versus host disease has been reported in an alemtuzumab-treated oncology patient.
Infusion-associated reactions: Serious and sometimes fatal IARs including bronchospasm, hypoxia, syncope, pulmonary infiltrates, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, arrhythmias, acute cardiac insufficiency, and cardiac arrest have been observed in non-MS patients treated with alemtuzumab at higher and more frequent doses than used in MS. Severe anaphylaxis and other hypersensitivity reactions, including anaphylactic shock and angioedema have also been reported.
Infections and infestations: Serious and sometimes fatal viral, bacterial, protozoan, and fungal infections, including those due to reactivation of latent infections, have been reported in non-MS patients treated with alemtuzumab at higher and more frequent doses than used in MS.
Blood and lymphatic system disorders: Severe bleeding reactions have been reported in non-MS patients.
Cardiac disorders: Congestive heart failure, cardiomyopathy, and decreased ejection fraction have been reported in alemtuzumab-treated non-MS patients previously treated with potentially cardiotoxic agents.
Epstein-Barr Virus-associated lymphoproliferative disorders: Epstein-Barr Virus-associated lymphoproliferative disorders have been observed outside company-sponsored studies.
Lemtrada contains sodium and potassium: This medicine contains less than 1 mmol potassium (39 mg) per infusion, i.e. it is essentially 'potassium-free'.
This medicine contains less than 1 mmol sodium (23 mg) per infusion, i.e. it is essentially 'sodium-free'.
Effects on ability to drive and use machines: LEMTRADA has minor influence on the ability to drive and use machines. Most patients experience IARs which occur during or within 24 hours after treatment with LEMTRADA.
Some of the IARs (e.g. dizziness) could temporarily impact the patient's ability to drive or use machines and caution should be exercised until these are resolved.