JINARC (tolvaptan) Healthcare professional educational guide

Transcription

1 JINARC (tolvaptan) Healthcare professional educational guide

2 Contents Abbreviations 3 What is the purpose of this brochure? 4 What is JINARC? What is JINARC indicated for? When should treatment not be initiated with JINARC? 5 What dose of JINARC should I prescribe? What are the special warnings and precautions for use? 6 Do I need to adjust the dose of JINARC for patients 8 with renal or hepatic impairment or for elderly patients? How should I manage patients with existing hepatic impairment? Prior to initiation During the first 18 months of treatment What safety issues should I discuss with patients 9 taking JINARC? Liver injury Water loss Skin neoplasm Glaucoma Overdose Fertility, pregnancy and lactation 10 Pregnancy Lactation and breast-feeding Fertility What other tools are available to support 11 the safe use of JINARC? Prescribing checklist Patient/carer education brochure Patient alert card Patient safety information leaflet How should I report adverse drug reactions, pregnancy and pregnancy outcomes with JINARC? Where can I obtain further information? 2

3 Abbreviations ADPKD Autosomal dominant polycystic kidney disease ALT AST AP AUC BT CKD egfr HCP INR SmPC WCBP ULN Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase Area under the curve Bilirubin-total Chronic kidney disease Estimated glomerular filtration rate Healthcare professional International normalised ratio Summary of Product Characteristics Women of child bearing potential Upper Limit of Normal 3

4 What is the purpose of this brochure? This brochure is provided by Otsuka Pharmaceuticals Ltd for prescribers and other healthcare professionals (HCPs) who are involved in the treatment of patients with autosomal dominant polycystic kidney disease (ADPKD) using JINARC (tolvaptan). This brochure will enable you to: understand what JINARC is indicated for and how it should be used be aware of important side effects of JINARC and how they can be prevented, identified and managed provide important safety information to your patients be aware of documents available that provide information on JINARC and their purpose be aware of the mechanism to report adverse events. This document summarises important information about JINARC. This does not replace the Summary of Product Characteristics, which should be read thoroughly before prescribing or dispensing JINARC. The patient should also be advised to read the Patient Information Leaflet. What is JINARC? JINARC contains tolvaptan, which blocks the effects of vasopressin at the V 2 receptor in the kidney. Vasopressin is responsible for water reabsorption and in patients with ADPKD it promotes cyst cell proliferation and secretion of fluid into the cysts. Preclinical studies showed that blocking vasopressin activity slows and/or stops cystogenesis and associated consequences in ADPKD models. Data from clinical trials demonstrate that JINARC slows cyst growth and decline in renal function. 1 What is JINARC indicated for? JINARC (tolvaptan) is indicated to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with CKD stage 1 to 4 at initiation of treatment with evidence of rapidly progressing disease. The safety and efficacy of JINARC in CKD stage 5 have not been adequately explored and therefore JINARC treatment should be discontinued if renal insufficiency progresses to CKD stage Torres VE et al. N Engl J Med 2012;367(25):

5 When should treatment not be initiated with JINARC? JINARC should not be used in patients with any of the following: elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of JINARC hypersensitivity to the active substance or to any of the excipients (maize starch, hydroxypropylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, indigo carmine (E132) aluminium lake) or to benzazepine or benzazepine derivatives volume depletion anuria hypernatraemia inability to perceive or respond to thirst pregnant or breastfeeding (female patients trying to become pregnant). What dose of JINARC should I prescribe? The initial dosage for JINARC is 60 mg per day as a split-dose regimen of 45 mg + 15 mg (45 mg taken upon waking and 15 mg taken 8 hours later) Up titration to a split-dose regime of 90 mg (60 mg + 30 mg) per day, if tolerated, with at least a week after initiation of the starting dose Further up titration to a split-dose regime of 120 mg (90 mg + 30 mg) per day, if tolerated, should be attempted with at least weekly intervals between titration steps. The morning dose of JINARC is to be taken at least 30 minutes before the morning meal. The second daily dose can be taken with or without food. Therapy must be interrupted if the ability to drink or the accessibility to water is limited. Patients must be instructed to drink sufficient amounts of water or other aqueous fluids. The aim of dose titration is to block activity of vasopressin at the renal V 2 receptor as completely and constantly as possible while maintaining acceptable fluid balance. Dose titration should be performed carefully to ensure that high doses are not poorly tolerated through too rapid up-titration. Patients should be maintained on the highest tolerated dose. In patients taking strong CYP3A inhibitors, JINARC should be administered once daily in doses of 15 mg or 30 mg. In patients taking moderate CYP3A inhibitors, JINARC split dose should be reduced: mg (for the mg dose), mg (for the mg), mg (for the mg dose). Concomitant administration of JINARC with potent CYP3A inducers (e.g., rifampicin, rifabutin, rifapentin, phenytoin, carbamazepine, and St. John s Wort) is to be avoided. 5

6 What are the special warnings and precautions for use? JINARC should be used with caution if any of the following apply: Condition Raised liver enzymes (AST and/or ALT stabilised at no greater than 3 x ULN) Severe hepatic impairment Cirrhosis Details JINARC has been associated with idiosyncratic elevations of blood ALT and AST with infrequent cases of concomitant elevations in BT. In post-marketing experience with JINARC in ADPKD, acute liver failure requiring liver transplantation has been reported. In patients with severe hepatic impairment the benefits and risks of treatment with JINARC must be evaluated carefully Limited access to water and dehydration JINARC may cause adverse reactions related to water loss such as thirst, polyuria, nocturia, and pollakiuria. Administration of JINARC induces copious aquaresis and may cause dehydration and increases in serum sodium. JINARC is contraindicated in hypernatraemic patients Partial obstruction of urinary outflow (e.g. prostatic hypertrophy) Patients with partial obstruction of urinary outflow, for example patients with prostatic hypertrophy or impairment of micturition, have an increased risk of developing acute retention Fluid and electrolyte imbalance Administration of JINARC induces copious aquaresis and may cause dehydration and increases in serum sodium. JINARC is contraindicated in hypernatraemic patients Serum sodium abnormalities Pretreatment sodium abnormalities (hyponatraemia or hypernatraemia) must be corrected prior to initiation with JINARC therapy Anaphylaxis Anaphylaxis has been reported very rarely following administration of JINARC after first administration. Patients with known hypersensitivity reactions to benzazepines or benzazepine derivatives may be at risk of hypesensitivity reaction Lactose and galactose intolerance JINARC contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine Diabetes mellitus JINARC may cause hyperglycaemia. Therefore, diabetic patients treated with JINARC must be managed cautiously. In particular this applies to patients with inadequately controlled type II diabetes Elevated uric acid concentration Decreased uric acid clearance by the kidney is a known effect of JINARC Medicines likely to interact with JINARC: CYP3A inhibitors CYP3A inducers CYP3A substrates P-gp substrates Vasopressin analogues Drugs increasing serum sodium concentration Diuretics Concomitant use of medicinal products that are strong or moderate CYP3A inhibitors (e.g. ketoconazole, fluconazole, grapefruit juice) increases JINARC exposure Concomitant use of medicinal products that are potent CYP3A (e.g rifampin) inducers will decrease JINARC exposure and efficacy JINARC can potentially increase exposure to CYP3A substrates (e.g. warfarin, amiodarone) JINARC may increase concentrations pf P-gp substrates (e.g digoxin, dabigatran) The effect of vasopressin analogues such as desmopressin may be attenuated in patients using such analogues to prevent or control bleeding when co-administered with JINARC (see SmPC for further examples of drugs likely to interact with JINARC) Effect of JINARC on glomerular filtration rate (GFR) A reversible reduction in GFR has been observed in ADPKD trials at the initiation of tolvaptan treatment. 6

7 Monitoring Blood tests for hepatic transaminases and bilirubin should be conducted before starting and regularly throughout treatment. See Section 4.4 of the JINARC SmPC for full details Patients must have access to water (or other aqueous fluids) and be able to drink sufficient amounts of these fluids. Additionally, patients have to drink 1-2 glasses of fluid before bedtime regardless of perceived thirst and replenish fluids overnight with each episode of nocturia. Volume status must be monitored in patients taking JINARC because treatment may result in severe dehydration which increases the risk of renal dysfunction. Symptoms of dehydration may include increase thirst, dry mouth, feeling tired or sleepy, decreased urination, headache, dry skin, dizziness, rapid heart rate, confusion and poor skin elasticity Good urinary output must be confirmed before starting, and during treatment with JINARC Serum creatinine, electrolytes and symptoms of electrolyte imbalances (e.g. dizziness, fainting, palpitations, confusion, weakness, gait instability, hyper-reflexia, seizures, coma) have to be assessed prior to and after starting JINARC to monitor for dehydration. Fluid and electrolyte status must be monitored in all patients. During long-term treatment electrolytes have to be monitored at least every three months Normal serum sodium levels before initiating therapy with JINARC If an anaphylactic reaction or other serious allergic reactions occur, administration of JINARC must be discontinued immediately and appropriate therapy initiated. Since hypersensitivity is a contraindication, treatment must never be restarted after an anaphylactic reaction or other serious allergic reactions Diabetic patients with an elevated glucose concentration (e.g. in excess of 300 mg/dl) may present with pseudohyponatraemia. This condition must be excluded prior and during treatment with JINARC Uric acid concentrations should be evaluated prior to starting JINARC therapy and as indicated during treatment based on symptoms Dose reduction of JINARC is recommended for patients while taking strong or moderate CYP3A inhibitors. JINARC should not be taken with grapefruit juice Concomitant administration of JINARC with potent CYP3A inducers (e.g., rifampin, rifabutin, rifapentin, phenytoin, carbamazepine, and St John s Wort) should be avoided Patients receiving digoxin or other narrow therapeutic P-gp substrates (e.g. dabigatran) must be managed cautiously and evaluated for excessive effects when treated with JINARC Concomitant use of JINARC with medicinal products that increase serum sodium concentration may result in a higher risk for developing hypernatraemia While there does not appear to be a synergistic or additive effect of concomitant use of JINARC with loop and thiazide diuretics, each class of agent has the potential to lead to severe dehydration, which constitutes a risk factor for renal dysfunction. If dehydration or renal dysfunction becomes evident, appropriate action must be taken which may include the need to interrupt or reduce doses of JINARC and/or diuretics and increased fluid intake. Other potential causes of renal dysfunction or dehydration must be evaluated and addressed. See Section 4.5 of the JINARC SmPC for full details 7

8 Do I need to adjust the dose of JINARC for patients with renal or hepatic impairment or for elderly patients? JINARC is contraindicated in anuric patients. Dose adjustment is not needed in patients with renal impairment although no studies have been conducted with creatinine clearance less than 10mL/min or on dialysis. The risk of hepatic damage in patients with severely reduced renal function (i.e. egfr < 20) may be increased; these patients should be carefully monitored for hepatotoxicity. Dose adjustment is not needed in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). Limited information is available in patients with severe hepatic impairment (Child-Pugh class C). These patients should be managed cautiously and liver enzymes should be monitored regularly. JINARC should be used in cirrhotic patients only when the need to treat outweighs the risk of treatment. In patients with severe hepatic impairment the benefits and risks of treatment with JINARC must be evaluated carefully. Patients must be managed carefully and liver enzymes must be monitored regularly. JINARC is contraindicated in patients with elevated liver enzymes and/or signs of liver injury that meet the criteria for permanent discontinuation. Increasing age does not appear to have an effect on JINARC plasma concentrations. However, the safety and effectiveness of JINARC in ADPKD patients aged over 50 has not yet been established. How should I manage patients with existing hepatic impairment? To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminases and bilirubin is required prior to initiation of JINARC, then: continuing monthly for 18 months after 18 months of therapy, at least 3 monthly or as indicated. Prior to initiation If a patient has abnormal blood ALT, AST or BT levels prior to initiation of treatment which fulfil the criteria for permanent discontinuation, the use of JINARC is contraindicated. In case of abnormal baseline levels below the limits for permanent discontinuation, treatment can only be initiated if the potential benefits of treatment outweigh the potential risks and liver function monitoring must continue at increased time frequency. During the first 18 months of treatment During the first 18 months of treatment, JINARC can only be prescribed to patients whose physician has determined that monitored liver function supports continued therapy. The following information is provided here to assist you in managing the patient. At the onset of symptoms or signs consistent with hepatic injury or if clinically significant abnormal ALT or AST increases are detected during treatment, JINARC administration must be interrupted immediately and repeat tests including ALT, AST, BT and alkaline phosphatase (AP) must be obtained as soon as possible (ideally within hours). Testing must continue at increased time frequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point JINARC may be reinitiated. 8 JINARC therapy should be interrupted upon confirmation of sustained or increasing transaminase levels and permanently discontinued if significant increases and/or clinical symptoms of hepatic injury persist. Recommended guidelines for permanent discontinuation include:

9 ALT or AST >8 x ULN ALT or AST >5 x ULN for more than 2 weeks ALT or AST >3 x ULN and BT >2 x ULN or international normalised ratio (INR) >1.5 ALT or AST >3 x ULN with persistent symptoms of hepatic injury (fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice). If ALT and AST levels remain below 3 times the ULN, JINARC therapy may be cautiously restarted, with frequent monitoring at the same or lower doses, as transaminase levels appear to stabilise during continued therapy in some patients. A JINARC prescribing checklist has been developed to help you decide if it is appropriate to continue treatment in patients exhibiting signs and symptoms of liver injury and elevated liver enzymes. It summarises the information above. It is important to report adverse events involving liver injury, including (and especially) any AST or ALT rise exceeding 3 x ULN. Adverse events should be reported; please find below how to report an adverse event. Adverse events should be reported. Reporting forms, on-line reporting and information can be found at Adverse events should also be reported to Otsuka at opuksafety@otsuka.co.uk or call What safety issues should I discuss with patients taking JINARC? Liver injury Patients should be informed about regular blood testing required to monitor and manage the risk of liver injury while taking JINARC. Monitoring for symptoms that may indicate liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, flu-like syndrome [joint and muscle pain with fever], rash, pruritus, icterus, dark urine or jaundice) should also be discussed. Patients should be advised to report these side effects to their doctor immediately if they occur. Water loss JINARC may cause undesirable effects related to water loss such as thirst, polyuria, nocturia, and pollakiuria. Patients should be instructed to drink water or other aqueous fluids ahead of thirst, in order to avoid excessive thirst or dehydration. Additionally, patients should be advised to drink 1-2 glasses of fluid before bedtime regardless of perceived thirst, and to replenish fluids overnight with each episode of nocturia. Grapefruit juice should not be taken as it may increase chances of side effects. It should be advised that special care should be taken in situations which increase chances of becoming dehydrated such as high temperature, vomiting or diarrhoea. The patient should be advised to seek medical attention if they suspect they are becoming dehydrated. Skin neoplasm In controlled clinical trials for JINARC, treated patients experienced a higher frequency of skin neoplasms (in particular basal cell carcinoma) compared to placebo. Although a causal relationship has not been established between JINARC and the higher incidence of skin neoplasms, appropriate regular skin examinations and management should be considered for patients before and during treatment with JINARC. 9

10 Glaucoma In controlled clinical trials for JINARC, glaucoma and increased intraocular pressure were observed in a greater proportion of patients treated with JINARC than in those treated with placebo, however, the frequency of glaucoma and increased intraocular pressure in both groups was low. Although a causal association between treatment with JINARC and the occurrence of glaucoma was not evident, periodic eye examinations should be considered before and during treatment with JINARC. Overdose There is no specific antidote for JINARC intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst and dehydration/hypovolemia. Profuse and prolonged aquaresis is anticipated on overdose. Assess vital signs, electrolyte concentrations, ECG and fluid status. Continue replacing water and electrolytes until aquaresis abates. Dialysis may not be effective in removing JINARC. Fertility, pregnancy and lactation Pregnancy JINARC is contraindicated during conception and pregnancy as it may result in developmental abnormalities in the foetus. Women of child-bearing potential (WCBP) should be advised to use one effective method of contraception for at least 4 weeks before starting therapy, during therapy and even in the case of dose interruptions, and for at least a further 4 weeks after stopping JINARC. Female patients should be advised to report to the treating physician immediately if they are pregnant or think they may be pregnant while taking JINARC or within 30 days after stopping JINARC. Pregnancy and pregnancy outcomes should be reported; please find below how to report them. Lactation and breast-feeding It is unknown whether JINARC is excreted in human breast milk. Studies in rats have shown excretion of JINARC in milk. JINARC is contraindicated while breastfeeding. Women should be advised not to breastfeed while taking JINARC and for one month after stopping JINARC. Fertility Two fertility studies in rats showed effects on the parental generation (decreased food consumption and body weight gain, salivation), but JINARC did not affect reproductive performance in males and there were no effects on the foetuses. In females, abnormal oestrus cycles were seen in both studies. The no observed adverse effect level (NOAEL) for effects on reproduction in females (100 mg/kg/day) was about 8-times the maximum human recommended dose of 120 mg/day on a mg/m 2 basis. The potential risk for humans is unknown. Teratogenicity was noted in rabbits given 1,000 mg/kg/day (7.5 times the exposure from the 120 mg/day human dose on an AUC basis). No teratogenic effects were seen in rabbits at 300 mg/kg/day (about 1.25 to 2.65 times the exposure in humans at the 120 mg/day dose, based on AUC). 10

11 What other tools are available to support the safe use of JINARC? In addition to the JINARC SmPC and this brochure, other items available to support HCPs and patients use of JINARC include a prescribing checklist, a patient/carer education brochure, a patient alert card and a patient safety information leaflet. These are described in more detail below. Prescribing checklist A prescribing checklist has been made available and is designed to help you assess the suitability of patients who have been identified as candidates for JINARC therapy, as well as their suitability for ongoing treatment. The checklist can be used at treatment initiation and regularly thereafter to help you monitor patients, to support the appropriate use of JINARC and to minimise the risk to patients. Patient/carer education brochure The patient education brochure contains a summary of the key information that the patient should be aware of while on JINARC therapy. It should be given to patients so they can learn more about dosing plan, correct intake, the most important safety issues to be aware of while taking JINARC and monitoring requirements. The patient education brochure also advises patients to contact their prescribing doctor if they are concerned that they may be experiencing signs and symptoms of hepatic injury or severe dehydration on treatment. Patient alert card The patient alert card contains important safety information about JINARC for patients and emergency carers. It includes information on hepatotoxicity, severe dehydration and advice should such symptoms occur. The patient alert card should be filled out and given to the patient by their prescribing doctor or nurse. The patient should keep it with them in their wallet or bag at all times. Patient safety information leaflet This leaflet should be given to patients and it is intended to provide patients with important safety information about JINARC with regards to potential liver injury, fertility, pregnancy and breast-feeding. How should I report adverse drug reactions, pregnancy and pregnancy outcomes with JINARC? Adverse events should be reported. Reporting forms, on-line reporting and information can be found at Adverse events should also be reported to Otsuka at medical.information@otsuka-europe.com or by calling Pregnancy and pregnancy outcomes should also be reported using the same details provided above. Where can I obtain further information? For further information, please contact Otsuka Medical Information at medinfo@otsuka.co.uk or call Please refer to JINARC SmPC available at 11

12 November OPUK/1118/JIN/1661.