Niranib Niraparib 100 mg Everest Pharmaceuticals Ltd. Bangladesh COMPOSITION NIRANIB Capsule: Each capsule contains Niraparib Tosylate Monohydrate INN equivalent to Niraparib 100 mg INDICATIONS AND USAGE NIRANIB is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. DOSAGE AND ADMINISTRATION The recommended dose of Niraparib as monotherapy is 300 mp (three 100 mp capsules) taken orally once daily. Instruct patients to take their dose of Niraparib at approximately the same time each day. Each capsule should be swallowed whole. Niraparib may be taken with or without food. Bedtime administration may be a potential method for managing nausea. Patients should start treatment with Niraparib no later than 8 weeks after their most recent platinum-containing regimen. Niraparib treatment should be continued until disease progres- sion or unacceptable toxicity. In the case of a missed dose of Niraparib, instruct patients to take their next dose at its regularly scheduled time If a patient vomits or misses a dose of Niraparib, an additional dose should not be taken. Dose Adjustments for Adverse Reactions To manage adverse reactions, consider interruption of treatment, dose reduction or dose discontinuation. The recommended dose modifications for adverse reactions are listed in Tables 1, 2 and 3. Table 1: Recommended dose modifications for adverse reactions Dose level Dose Starting dose 300 mg/day (three 100 mg capsules) First dose reduction 200 mg/day (two 100 mg capsules) Second dose reduction 100 mg/day* (one 100 mg capsule) ”If further dose i eduction Leluw 100 mg/day is required, discontinue Nirapai ib. Table 2: Dose modifications for non-hematologic adverse reactions Non-hematologic CTCAE* > Grade 3 adverse reaction where prophylaxis is not considered feasible or adverse reaction persists despite treatment. Withhold NIRANIB tor a maximum of 28 days or until resolution of adverse reaction. Resume NIRANIB at a reduced dose per Table 1. Up to 2 dose reductions are permitted. CTCAE > Grade 3 treatment-related adverse reaction lasting more than 28 days while patient is administered NIRANIB 100 mg/day. Discontinue medication. *CTCAE-Common Tei min‹nIr›gy Criteria fr›r Adverse Events Table 3: Dose modifications for hematologic adverse reactions Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment and periodically after this time. Platelet count <1OO,000/pL First occurrence Withhold NIRANIB for a maximum of 28 days and monitor blood counts weekly Until plat9I 9t COUrItS r9tUrn tO > 100,000/pL. Resume NIRANIB at same or reduced dose per Table 1. If platelet count is <75,00O/q L, resume at a reduced dose. Second occurrence: Withhold NIRANIB for a maximum of 28 days and monitor blood counts weekly until platelet counts return to > 1O0,000/pL. Resume NIRANIB at a reduced dose per Table 1. Discontinue NIRANIB if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period, or if the patient has already undergone dose reduction to 100 mg once daily.* Neutrophil <1,OO0/pL or Hemoglobin <8 g/dL Withhold NIRANIB for a maximum of 28 days and monitor blood counts weekly until neutrophil counts return to >1,50O/ML or hemoglobin returns to >9 g/dL. Resume NIRANIB at a reduced dose per Table 1. Discontinue NIRANIB if neutrophils and/or hemoglobin have not returned to accept- able levels within 28 days of the dose interruption period, or if the patient has already undergone dose reduction to 100 mg once daily.* Hematologic adverse reaction requiring transfusion For patients with platelet count <10,000/pL, platelet transfusion should be consid- ered. If there are other risk factors such as co-administra- tion of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or transfusion at a higher platelet coUnt. Resume NIRANIB at a reduced dose. *If myeIr›dyspIastic syndi ame or acute myeIr›id leukemia (MDS/AML) is cr›nfirmed, discOntinue Niraparib.Patients with low body weight Approximately 25% of patients in the NOVA study weighed less than 58 kg, and approximately 25% of patients weighed more than 77 kg. The incidence of Grade 3 or 4 ADRs was greater among low body weight patients (78%) than high body weight patients (53%). Only 13% of low body weight patients remained at a dose of 300 mg beyond Cycle 3. A starting dose of 200 mg for patients weighing less than 58 kg may be considered.Elderly No dose adjustment is necessary for elderly patients (> 65 years). There are limited clinical data in patients aged 75 or over. Renal impairment No dose adjustment is necessary for patients with mild to moderate renal impairment. There are no data in patients with severe renal impairment or end stage renal disease undergoing haemodialysis; use with caution in these patients. Hepatic impairment No dose adjustment is needed in patients with mild to moderate hepatic impairment. There are no data in patients with severe hepatic impairment; use with caution in these patients. Greve>t Paediatric population The safety and efficacy of niraparib in children and adolescents below 18 years of age have not yet been established. No data are available Method of administration Oral use. The capsules should be swallowed whole with water. The capsules should not be shewed or crushed. Niraparib can be taken without regard to meals. CONTRAINDICATION Hypersensitivity to the active substance or to any of the excipients & breast-feeding. WARNINGS & PRECAUTIONS Myelodysplastic syndromelacute myeloid leukaemia Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), including cases with fatal outcome, have been reported in a small number of patients who received Niraparib or placebo. In the pivotal Phase 3 international trial (ENGOT-OV16), the incidence of MDS/AML in patients who received niraparib (1.4%) was similar to that in patients who received placebo (1.1%). Overall, MDS/AML has been reported in 7 out of 751 (0.9%) patients treated with Niraparib in clinical studies. The duration of Niraparib treatment in patients prior to develop- ing MDS/AML varied from month to > 2 years. The cases were typical of secondary, cancer therapy-related MDS/AML. All patients had received multiple platinum-containing chemothera- py regimens and many had also received other DNA damaging agents and radiotherapy. Some of the patients had a history of bone marrow dysplasia. If MDS and/or AML are confirmed while on treatment with Niraparib, treatment should be discontinued and the patient treated appropriately. Hypertension including hypertensive crisis Hypertension, including hypertensive crisis, has been reported with the use of Niraparib. Pre-existing hypertension should be adequately controlled before starting Niraparib treatment. Blood pressure should be monitored monthly for the first year and periodically thereafter during treatment with Niraparib. Hypertension should be medically managed with antihyperten- sive medicinal products as well as adjustment of the Niraparib dose, if necessary. In the clinical programme, blood pressure measurements were obtained on Day 1 of each 28-day cycle while the patient remained on Niraparib. In most cases, hypertension was controlled adequately using standard antihypertensive treatment with or without Niraparib dose adjustment. Niraparib should be discontinued in case of hypertensive crisis or if medically significant hypertension cannot be adequately controlled with antihypertensive therapy. Pregnancylcontraception Niraparib should not be used during pregnancy or in women of childbearing potential not willing to use reliable contraception during therapy and for 1 month after receiving the last dose of Niraparib. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Lactose Niraparib hard capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Tartrazine (E 102) This medicinal product contains tartrazine (E 102), which may cause allergic reactions. ADVERSE REACTIONS In the pivotal ENGOT-OV16 study, adverse reactions (ADRs) occurring > 10% of patients receiving Niraparib monotherapy were nausea, thrombocytopenia, fatigue/asthenia, anaemia, constipation, vomiting, abdominal pain, neutropenia, insomnia, headache, decreased appetite, nasopharyngitis, diarrhoea, dyspnea, hypertension, dyspepsia, back pain, dizziness, cough, urinary tract infection, arthralgia, palpitations, and dysgeusia. The most common serious adverse reactions > 1% (treatment- emergent frequencies) were thrombocytopenia and anaemia. DRUG INTERACTIONS Pharmacodynamic interactions The combination of Niraparib with vaccines or immunosuppres- sant agents has not been studied The data on niraparib in combination with cytotoxic medicinal products are limited. Therefore, caution should be taken if niraparib is used in combination with vaccines, immunosuppres- sant agents or with other cytotoxic medicinal products. Pharmacokinetic interactions Effect of other medicinal products on Niraparib Niraparib as a substrate of CYPs (CYP1A2 and CYP3A4) Niraparib is a substrate of carboxylesterases (CEs) and UDP-glucuronosyltransferases (UGTs) in vivo. Oxidative metabolism of niraparib is minimal in vivo. No dose adjustment for Niraparib is required when administered concomitantly with medicinal products known to inhibit (e.g. itraconazole, ritonavir, and clarithromycin) or induce CYP enzymes (e.g. rifampin, carbamazepine and phenytoin). Niraparib as a substrate of efllux transporters (P-gp, BCRP and MATE1I2) Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, due to its high permeability and bioavailability, the risk of clinically relevant interactions with medicinal products that inhibit these transport- ers is unlikely. Therefore, no dose adjustment for Niraparib is required when administered concomitantly with medicinal products known to inhibit P-gp (e.g. amiodarone, verapamil) or BCRP (e.g. osimertinib, velpatasvir, and eltrombopag). Niraparib is not a substrate of bile salt export pump (BSEP). The major primary metabolite M1 is not a substrate of P-gp, BCRP or BSEP. Niraparib is not a substrate of MATE 1 or 2, while M1 is a substrate of both. Niraparib as a substrate of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1) Neither Niraparib nor MI is a substrate of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1). No dose adjustment for Niraparib is required when administered concomitantly with medicinal products known to inhibit OATP1B1 or 1B3 (e.g. gemfibrozil, ritonavir) or OCT1 (e.g. dolutegravir) uptake transporters Niraparib as a substrate of renal uptake transporters (OAT1, OAT3 and OCT2) Neither Niraparib nor MI is a substrate of organic anion transporter 1 (OAT1), 3 (OAT3) and organic cation transporter 2 (OCT2). No dose adjustment for Niraparib is required when administered concomitantly with medicinal products known to inhibit OAT1 (e.g. probenecid) or OAT3 (e.g. probenecid, diclofenac) or OCT2 (e.g. cimetidine, quinidine) uptake transporters. Effect of niraparib on other medicinal products Inhibition of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) Neither Niraparib nor MI is an inhibitor of any active NiraiÏ”ib Niraparibl00mg Even though inhibition of CYP3A4 in the liver is not expected, the potential to inhibit CYP3A4 at the intestinal level has not been established at relevant Niraparib concentrations. Therefore, caution is recommended when Niraparib is combined with active substances the metabolism of which is CYP3A4-dependent and, notably, those having a narrow therapeutic range (e.g. ciclospo- rin, tacrolimus, alfentanil, ergotamine, pimozide, quetiapine and halofantrine). Induction of CYPs (CYP1 A2 and CYP3A4) Neither Niraparib nor MI is a CYP3A4 inducer in vitro. In vitro, Niraparib weakly induces CYP1A2 at high concentrations and the clinical relevance of this effect would not be completely ruled out. M1 is not a CYP1A2 inducer. Therefore, caution is recommended when niraparib is combined with active substances the metabolism of which is CYPlA2-dependent and, notably, those having a narrow therapeutic range (e.g. clozap- ine, theophylline and ropinirole). Inhibition of efflux transporters (P-gp, BCRP, BSEP, and MATE1I2) Niraparib is not an inhibitor of BSEP. In vitro, Niraparib inhibits P-gp very weakly and BCRP with an lC50 = 161 pM and 5.8 pM, respectively. Therefore, a clinically meaningful interaction related to an inhibition of these efflux transporters although unlikely, cannot be excluded. Caution is then recommended when Niraparib is combined with substrates of BCRP (irinotecan, rosuvastatin, simvastatin, atorvastatin and methotrexate). Niraparib is an inhibitor of MATE1 and -2 with IC50 of 0.18 PM and < 0.14 pM, respectively. Increased plasma concentrations of co-administered medicinal products that are substrates of these transporters (e.g. metformin) cannot be excluded.The major primary metabolite MI does not appear to be an inhibitor of P-gp, BCRP, BSEP or MATE1/2.Inhibition of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1) Neither Niraparib nor MI is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1 ) or 1B3 (OATP1B3).In vitro, niraparib weakly inhibits the organic cation transporter 1 (OCT1) with an IC50 = 34.4 pM. Caution is recommended when Niraparib is combined with active substances that undergo an uptake transport by OCT1 such as metformin.Inhi n of renal uptake transporters (OAT1, OAT3, and OCT2) Neither Niraparib nor M1 inhibits organic anion transporter 1 (OAT1), 3 (OAT3) and organic cation transporter 2 (OCT2).AII clinical studies have only been performed in adults.USE IN SPECIFIC POPULATION Women of childbearing potentiallcontraception in females Women of childbearing potential should not become pregnant while on treatment and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Women of childbear- ing potential must use effective contraception during therapy and for 1 month after receiving the last dose of NiraparibPregnancy There are no or limited amount of data from the use of Niraparib in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted. However, based on its mechanism of action, niraparib could cause embryonic or foetal harm, including embryo-lethal and teratogenic effects, when administered to a pregnant woman. Niraparib should not be used during pregnancy.Breast-feeding It is unknown whether niraparib or its metabolites are excreted in human milk. Breast-feeding is contraindicated during adminis- tration of Niraparib and for 1 month after receiving the last doseFertility There are no clinical data on fertility. A reversible reduction of spermatogenesis was observed in rats and dogs.Pediatric Use Safety and effectiveness of Niraparib have not been established in pediatric patients.Geriatric Use In Trial 1 (NOVA), 35% of patients were aged >65 years and 8% were aged >75 years. No overall differences in safety and effectiveness of Niraparib were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No dose adjustment is necessary for patients with mild (CLcr:60 to 89mL/min) to moderate (CLcr:30 to 59mL/min) renal impairment. The degree of renal impairment was determined by creatinine clearance as estimated by the Cockcroft-Gault equation. The safety of NIRAPARIB in patients with severe renal impairment or end stage renal disease undergoing hemodialysis is unknown. Hepatic Impairment No dose adjustment is needed in patients with mild hepatic impairment according to the National Cancer Institute- Organ Dysfunction Working Group (NCI-ODWG) criteria. The safety of Niraparib in patients with moderate to severe hepatic impairment is unknown. OVERDOSE There is no specific treatment in the event of Niraparib overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow General supportive measures and should treat symptomatically. DESCRIPTION Niraparib is an orally available poly (ADP-ribose) polymerase (PARP) inhibitor. The chemical name for Niraparib tosylate monohydrate is 2-(4-[(3S)-piperidin-3-yljphenyl}-2H-indazole7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The molecular formula is C2gHggN4OsS and it has a molecular weight of 510.61 amu. The molecular structure is shown below: Niraparib tosylate monohydrate is a white to off-white, non-hy- groscopic crystalline solid. Niraparib solubility is p* independent below the pKa 9.95, with an aqueous free base solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological p* range. Each Niraparib capsule contains 159.4 mg Niraparib tosylate monohydrate equivalent to 100 mg Niraparib free base as the active ingredient. The inactive ingredients in the capsule till are magnesium stearate and lactose monohydrate. The capsule shell consists of titanium dioxide, gelatin in the white capsule body; and FD&C Blue #1, FD & C Red #3, FD & C Yellow #5 and gelatin in the purple capsule cap. The black printing ink consists Gre e>t of shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide and black iron oxide. The white printing ink consists of shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, povidone and titanium oxide. CLINICAL PHARMACOLOGY Mechanism of Action Niraparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased Niraparib-induced cytotox- icity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2. Pharmacodynamics The pharmacodynamic response of Niraparib has not been characterized. Cardiovascular Effects Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) [see Nonclinical Toxicology (13.2)]. In the NOVA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increas- es from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the Niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the Niraparib and placebo arms, respectively. Cardiac Electrophysiology The potential for QTc prolongation with Niraparib was evaluated !n a randomized, placebo-controlled trial in cancer patients (367 patients on Niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the trial following the treatment of Niraparib 300 mg once daily. Pharmacokinetics Following a single-dose administration of 300 mg Niraparib, the mean ( SD) peak plasma concentration (Cmax) was 804 ( 403) ng/mL. The systemic exposures (Cmax and AUC) of niraparib increased in a dose proportional manner with daily doses ranging from 30 mg (0.1 times the approved recommended dosage) to 400 mg (1.3 times the approved recommended dosage). The accumulation ratio of Niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg. Absorption The absolute b!oavailability of niraparib is approximately 73%. Following oral administration of Niraparib, peak plasma concen- tration, Cmax, is reached within 3 hours. Concomitant adminis- tration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not significantly affect the pharmacokinetics of Niraparib. Distribution Niraparib is 83.0% bound to human plasma proteins. The average ( SD) apparent volume of distribution (Vd/F) was 1220 ( 1114) L. In a population pharmacokinetic analysis, the Vd/F of Niraparib was 1074 L in cancer patients. Elimination Following multiple daily doses of 300 mp Niraparib, the mean half-life (t1/2) is 36 hours. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 Uh in cancer patients. Metabolism Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation. Excretion Following administration of a single oral 300 mg dose of radio-la- beled Niraparib, the average percent recovery of the adminis- tered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine and 38.8% (range 28.3% to 47.0%) in feces. In pooled samples collected over 6 days, unchanged Niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively. Specific Populations Age (18 to 65 years old), race/ethnicity and mild to moderate renal impairment had no clinically significant effect on the pharmacokinetics of Niraparib The effect of severe renal impairment or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of Niraparib is unknown. The effect of moderate or severe hepatic impairment on the pharmacokinetics of Niraparib is unknown NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Care/nogen/c/ty studies ñave not been conducted with Niraparib. Niraparib was clastogenic in an in vitro mammalian chromosom- al aberration assay and in an in vivo rat bone marrow micronu- cleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of Niraparib and indicates potential for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse mutation assay (Annes) test. Fertility studies in animals have not been conducted with Nirapa- rib. In repeat-dose oral toxicity studies, Niraparib was adminis- tered daily for up to 3 months duration in rats and dogs. Reduced sperm, spermatids and germ cells in epididymides and testes were observed at doses >10 mg/kg and >1.5 mg/kg !n rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.3 and 0.012 times, respec- tively, the human exposure (AUG0-24hr) at the recommended dose of 300 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped. PHARMACEUTICAL INFORMATION Storage Conditions Store in a cool and dry place. Do not store above 30”C. Do not take NIRANIB if it is suspected of having been exposed to temperatures greater than 40”C or 104” F. Keep NIRANIB out of the reach and sight of children HOW SUPPLIED NIRANIB Capsule: Each HDPE container contains 30 Capsules, each of which contains Niraparib INN 100 mg Patients with ECOG performance status 2 to 4 Clinical data are not available in patients with ECOG performance status 2 to 4. substance-metabolising CYP enzymes, namely CYP1A1/2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5. Manufactured By Everest Pharmaceuticals Ltd.