Polivy 30 mg/140 mg Solution

Polivy in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) is indicated for the treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

Polivy in combination with bendamustine and rituximab is indicated for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are not candidates for haematopoietic stem cell transplant.

General
Substitution by any other biological medicinal product requires the consent of the professional medical practitioner. In order to prevent medication errors, it is important to check the vial labels to ensure that the medicine being prepared and administered is Polivy. Polivy therapy should only be administered under the supervision of a healthcare professional experienced in the treatment of cancer patients. For information on rituximab, bendamustine, cyclophosphamide, doxorubicin, or prednisone, refer to their respective full professional information. Refer to Table 2 for dose modification recommendations for neutropenia and thrombocytopenia.

Posology
Diffuse large B-cell lymphoma
Previously untreated patients: The recommended dose of Polivy is 1,8 mg/kg given as an intravenous infusion every 21 days for 6 cycles in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP). Polivy, rituximab, cyclophosphamide, and doxorubicin can be administered in any order on Day 1 after the administration of prednisone. Prednisone is administered on Days 1 u2013 5 of each cycle. Cycles 7 and 8 consist of rituximab as monotherapy.
Relapsed or refractory patients: The recommended dose of Polivy is 1,8 mg/kg given as an intravenous infusion every 21 days in combination with bendamustine and rituximab for 6 cycles. Polivy, bendamustine, and rituximab can be administered in any order on Day 1 of each cycle. The recommended dose of bendamustine is 90 mg/mu00b2/day on Day 1 and 2 when administered with Polivy and rituximab.

Previously untreated and relapsed or refractory patients: If not already premedicated, administer premedication with an antihistamine and anti-pyretic to patients prior to administration of Polivy. The initial dose of Polivy should be administered as a 90-minute intravenous infusion. Patients should be monitored for infusion-related reactions during the infusion and for at least 90 minutes following completion of the initial dose. If the prior infusion was well tolerated, the subsequent dose of Polivy may be administered as a 30-minute infusion and patients should be monitored during the infusion and for at least 30 minutes after completion of the infusion.

Delayed or Missed Doses: If a planned dose of Polivy is missed, it should be administered as soon as possible and the schedule of administration should be adjusted to maintain a 21-day interval between doses.

Dose Modifications: The infusion rate of Polivy should be slowed or interrupted if the patient develops an infusion-related reaction. Discontinue Polivy immediately and permanently if the patient experiences a life-threatening reaction. There are different possible dose modifications for Polivy in patients with previously untreated DLBCL and those who are relapsed or refractory. For dose modifications to manage peripheral neuropathy see Table 1.

Hypersensitivity to the polatuzumab vedotin or to any of the excipients listed in section 6.1.

Traceability: In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

Sucrose: Contains sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose mal-absorption or sucrose-isomaltase insufficiency should not take Polivy.

Myelosuppression: Serious and severe neutropenia and febrile neutropenia have been reported in patients treated with Polivy as early as the first cycle of treatment (see 4.8 Undesirable Effects). Prophylactic G-CSF administration should be considered. Grade 3 or 4 thrombocytopenia or anemia can also occur with Polivy (see 4.8 Undesirable Effects). Complete blood counts should be monitored prior to each dose of Polivy. More frequent lab monitoring and/or Polivy delays or discontinuation should be considered in patients with Grade 3 or Grade 4 neutropenia and thrombocytopenia (see 4.2 Posology and method of administration).

Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially u2018sodium-freeu2019.

Peripheral Neuropathy: Peripheral neuropathy has been reported in patients treated with Polivy as early as the first cycle of treatment, and the risk increases with sequential doses (see 4.8 Undesirable effects). Patients with pre-existing peripheral neuropathy may experience worsening of this condition. Peripheral neuropathy reported with Polivy treatment is predominantly sensory peripheral neuropathy; however, motor and sensorimotor peripheral neuropathy have also been reported. Patients should be monitored for symptoms of peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, or gait disturbance. Patients experiencing new or worsening peripheral neuropathy may require a delay, dose reduction, or discontinuation of Polivy (see 4.2 Posology and method of administration).

Infections: Serious, life threatening, or fatal infections, including opportunistic infections, such as pneumonia (including pneumocystis jirovecii and other fungal pneumonia), bacteremia, sepsis, herpes infection, and cytomegalovirus infection have been reported in patients treated with Polivy (see 4.8 Undesirable Effects). Patients should be closely monitored during treatment for signs of bacterial, fungal, or viral infections. Anti-infective prophylaxis should be considered. Polivy and any concomitant chemotherapy should be discontinued in patients who develop serious infections.

Human Immunodeficiency Virus (HIV): Polivy has not been evaluated in patients with HIV. With regard to co-administration of CYP3A-inhibitors see section 4.5. Polivy has not been tested in patients with secondary immune deficiency due to HIV.

Human Immunodeficiency Virus (HIV) and Tuberculosis (TB) testing and risks of Polivy: A diagnosis of any form of active tuberculosis should be explicitly excluded in patients considered for treatment with Polivy. Furthermore, a history of previous tuberculosis, HIV-infection, or a diagnosis of latent TB infection pose a risk for reactivation of tuberculosis and appropriate preventive therapy is indicated, regardless of HIV-status. Diagnosis and treatment of latent infection, following national guidelines, should be initiated prior to use of Polivy. u201cPeople initiating Polivy treatment, who initially tested negative for active or latent tuberculosis, should be systematically tested for latent TB infection during treatment with Polivy, and preventive treatment instituted if indicated.

Immunization: Live or live-attenuated vaccines should not be given concurrently with the treatment. Studies have not been conducted in patients who recently received live vaccines.

Progressive Multifocal Leukoencephalopathy (PML): PML has been reported with Polivy treatment (see 4.8 Undesirable effects). Patients should be monitored closely for new or worsening neurological, cognitive, or behavioral changes suggestive of PML. Polivy and any concomitant chemotherapy should be held if PML is suspected and permanently discontinued if the diagnosis is confirmed.

Tumor Lysis Syndrome: Patients with high tumor burden and rapidly proliferative tumor may be at increased risk of tumor lysis syndrome. Appropriate measures in accordance with local guidelines should be taken prior to treatment with Polivy. Patients should be monitored closely for tumor lysis syndrome during treatment with Polivy.

Infusion-related reactions: Polivy can cause IRRs, including severe cases. Delayed IRRs as late as 24 hours after receiving Polivy have occurred. An antihistamine and antipyretic should be administered prior to the administration of Polivy, and patients should be monitored closely throughout the infusion. If an IRR occurs, the infusion should be interrupted and appropriate medical management should be instituted (see section 4.2).

Embryo-Fetal Toxicity: Based on the mechanism of action and nonclinical studies, Polivy can harmful to the fetus when administered to a pregnant woman. Advise a pregnant woman of the risk to the foetus. Females of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 9 months after the last dose. Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 6 months after the last dose (see Section 4.6 Fertility, pregnancy and lactation).

Hepatic Toxicity: Serious cases of hepatic toxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with Polivy. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Liver enzymes and bilirubin level should be monitored (see Section 4.2 Special Dosage Instructions, Hepatic Impairment).

No dedicated clinical interaction studies with Polivy in humans have been conducted. Medicines interactions with co-medications that are CYP3A inhibitors, inducers or substrates and co-medications that are P-gp inhibitors. Based on physiological-based pharmacokinetic (PBPK) model simulations of MMAE released from polatuzumab vedotin, strong CYP3A inhibitors (e.g., ketoconazole) may increase the area under the concentration-time curve (AUC) of unconjugated MMAE by 48%. Monitor patients receiving concomitant strong CYP3A inhibitors more closely for signs of toxicities. Strong CYP3A inducers (e.g., rifampin) may decrease the AUC of unconjugated MMAE by 49%. Unconjugated MMAE is not predicted to alter the AUC of concomitant medicines that are CYP3A substrates (e.g., midazolam). Strong CYP3A4 inducers (e.g., rifampicin, carbamezapine, phenobarbital, phenytoin, St Johnu2019s wort [Hypericum perforatum]) may decrease the exposure of unconjugated MMAE. Medicine interactions of rituximab, bendamustine, cyclophosphamide, and doxorubicin in combination with polatuzumab vedotin. The pharmacokinetics (PK) of rituximab, bendamustine, cyclophosphamide, and doxorubicin are not affected by co-administration with Polivy. Concomitant rituximab is associated with increased antibody conjugated MMAE (acMMAE) plasma AUC by 24% and decreased unconjugated MMAE plasma AUC by 37%, based on population PK analysis. The plasma AUC of acMMAE and unconjugated MMAE for Polivy plus R-CHP are in line with other studies of Polivy. No dose adjustment is required. Bendamustine does not affect acMMAE and unconjugated MMAE plasma AUC.

Fertility: Based on animal studies, Polivy may impair male reproductive function and fertility.
Contraception:
Females: Females of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 9 months after the last dose.
Males: Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 6 months after the last dose.
Pregnancy: Polivy is not recommended during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus. Polivy can cause foetal harm based on the animal studies and the medicineu2019s mechanism of action (see Section 5.1 Mechanism of Action).
Labor and Delivery: The safe use of Polivy during labor and delivery has not been established.
Lactation: It is not known whether polatuzumab vedotin is excreted in human breast milk. No studies have been conducted to assess the impact of Polivy on milk production or its presence in breast milk. Since many medicines are excreted in human milk and because of the potential for serious adverse reactions in breastfeeding infants due to Polivy, women should discontinue breastfeeding during Polivy treatment and for at least 3 months after the last dose.

Polivy may have a minor influence on the ability to drive and use machines. Infusion related reactions, peripheral neuropathy, fatigue, and dizziness may occur during treatment with Polivy (see section 4.4 Warnings and Precautions and 4.8 Undesirable Effects).

a. Summary of the Safety Profile: The safety of Polivy has been evaluated in 435 patients in Study GO39942 (POLARIX). The adverse drug reactions (ADRs) described in this section were identified based on the following: during treatment and follow-up of previously untreated DLBCL patients from the pivotal clinical trial POLARIX (GO39942), who received Polivy plus R-CHP (n=435) or R-CHOP (n=438). In the Polivy plus R-CHP group, 91,7% of patients received 6 cycles of Polivy versus 88,5% of patients who received 6 cycles of vincristine in the R-CHOP group. In previously untreated DLBCL patients treated with Polivy plus R-CHP: The most frequently-reported (u2265 30%) adverse drug reactions (ADRs) in patients treated with Polivy plus R-CHP for previously untreated DLBCL were neuropathy peripheral (52,9%), nausea (41,6%), neutropenia (38,4%), and diarrhoea (30,8%). Serious adverse reactions were reported in 24,1% of Polivy plus R-CHP treated patients. The most common serious adverse reactions reported in u2265 5% of patients were febrile neutropenia (10,6%) and pneumonia (5,3%). The ADRs leading to treatment regimen discontinuation in > 1% of patients treated with Polivy plus R-CHP was pneumonia (1,1%). The safety of Polivy has been evaluated in 151 patients in Study GO29365. The ADRs described in this section were identified: during treatment and follow-up of previously treated diffuse large B-cell lymphoma (DLBCL) patients (n=151) from the pivotal clinical trial GO29365. This includes run-in phase patients (n=6), randomised patients (n=39), and extension cohort patients (n=106) who received Polivy in combination with bendamustine and rituximab (BR) compared to randomised patients (n=39) who received BR alone. Patients in the Polivy treatment arms received a median of 5 cycles of treatment while randomised patients in the comparator arm received a median of 3 cycles of treatment. In previously treated DLBCL patients treated with Polivy plus BR: The most frequently reported (u2265 30%) ADRs (all grades) in patients treated with Polivy plus BR in previously treated DLBCL were neutropenia (45,7%), diarrhoea (35,8%), nausea (33,1%), thrombocytopenia (32,5%), anaemia (31,8%) and neuropathy peripheral (30,5%). Serious adverse reactions were reported in 41,7% of Polivy plus BR treated patients. The most common serious adverse reactions reported in > 5% of patients were febrile neutropenia (10,6%), sepsis (9,9%), pneumonia (8,6%) and pyrexia (7,9%). The ADR leading to treatment regimen discontinuation in > 5% of patients treated with Polivy plus BR was thrombocytopenia (7,9%).

b. Tabulated list of adverse reactions: The ADRs in 586 patients treated with Polivy are presented in Table 4. The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1,000 to < 1/100), rare (u2265 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

There is no specific information available on the management of overdose with Polivy. In the event of an overdose, patients should be closely monitored for signs and symptoms of toxicity and appropriate supportive care should be provided.