Aliqopa

 Recommended Dosage

The recommended dose of ALIQOPA is 60 mg administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Continue treatment until disease progression or unacceptable toxicity [see Warnings and Precautions ].

 Dose Modification for Moderate or Severe Hepatic Impairment

Reduce ALIQOPA dose to 45 mg in patients with moderate hepatic impairment (Child-Pugh B). Reduce ALIQOPA dose to 30 mg in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations ].

 Dose Modification for Use with Strong CYP3A Inhibitors

Reduce ALIQOPA dose to 45 mg if a strong CYP3A inhibitor must be used. Concomitant use of ALIQOPA with strong CYP3A inhibitors increases copanlisib exposure (AUC) and may increase the risk for toxicity [see Drug Interactions ].

 Dosage Modifications for Toxicities

Manage toxicities per Table 1 with dose reduction, treatment delay, or discontinuation of ALIQOPA. Discontinue ALIQOPA if life-threatening ALIQOPA-related toxicity occurs.

aEnsure a minimum of 7 days between any two consecutive infusions.

bNational Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.

cBoth systolic of less than 150 mmHg and diastolic of less than 90 mmHg are required.

 Preparation and Administration

For intravenous infusion only.

Administer ALIQOPA as a single agent, following reconstitution and dilution. Mix only with sterile 0.9% Sodium Chloride Injection, USP solution. Do not mix or inject ALIQOPA with other drugs or other diluents.

 Reconstitution Instructions

Reconstitute ALIQOPA with 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution leading to a concentration of 15 mg/mL.

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Withdraw 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution by using a 5 mL sterile syringe with needle.

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Inject the measured volume through the disinfected stopper surface into the vial of ALIQOPA.

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Dissolve the lyophilized solid by gently shaking the injection vial for 30 seconds.

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Allow to stand for one minute to let bubbles rise to the surface.

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Check if any undissolved substance is still seen. If yes, repeat the gentle shaking and settling procedure.

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Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After reconstitution, the solution should be colorless to slightly yellowish.

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Once the solution is free of visible particles, withdraw the reconstituted solution for further dilution.

 Dilution Instructions for Intravenous Use

Further dilute the reconstituted solution in 100 mL sterile 0.9% Sodium Chloride Injection, USP solution for injection. With a sterile syringe, withdraw the required amount of the reconstituted solution for the desired dosage:

60 mg: Withdraw 4 mL of the reconstituted solution with a sterile syringe.

45 mg: Withdraw 3 mL of the reconstituted solution with a sterile syringe.

30 mg: Withdraw 2 mL of the reconstituted solution with a sterile syringe.

Inject the contents of the syringe into the patient infusion bag of 100 mL sterile 0.9% Sodium Chloride Injection, USP solution. Mix the dose well by inverting.

Discard any unused reconstituted or diluted solution appropriately.

Use reconstituted and diluted ALIQOPA immediately or store the reconstituted solution in the vial or diluted solution in the infusion bag at 2°C to 8°C (36°F to 46°F) for up to 24 hours before use. Allow the product to adapt to room temperature before use following refrigeration. Avoid exposure of the diluted solution to direct sunlight.

 Pregnancy

 Lactation

Females and Males of Reproductive Potential

ALIQOPA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ].

 Pediatric Use

Safety and effectiveness of ALIQOPA have not been established in pediatric patients.

 Geriatric Use

No dosage adjustment of ALIQOPA is necessary in patients ≥65 years of age. Of 168 patients with follicular lymphoma and other hematologic malignancies treated with ALIQOPA, 48% were age 65 or older while 16% were age 75 or older. No clinically relevant differences in efficacy were observed between elderly and younger patients. In patients ≥65 years of age, 30% experienced serious adverse reactions and 21% experienced adverse reactions leading to discontinuation. In the patients <65 years of age, 23% experienced serious adverse reactions and 11% experienced adverse reactions leading to discontinuation.

Hepatic Impairment

Reduce ALIQOPA dose to 45 mg for patients with moderate hepatic impairment (Child-Pugh B). Reduce ALIQOPA dose to 30 mg for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration ]. No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤1 × upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN, or total bilirubin >1 to 1.5 × ULN and any AST) [see Clinical Pharmacology ].

 Infections

Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia [see Adverse Reactions ]. Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection [see Dosage and Administration ].

Serious pneumocystis jiroveci pneumonia (PJP) occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions ]. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk. Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis [see Dosage and Administration ].

Grade 1 or 2 cytomegalovirus (CMV) reactivation or infection has occurred in 0.97% of patients treated with ALIQOPA monotherapy. Monitor for CMV infection during treatment with ALIQOPA in patients with a history of CMV infection. For clinical CMV infection or viremia, withhold ALIQOPA until infection or viremia resolves. If ALIQOPA is resumed, administer at the previous dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly [see Dosage and Administration ].

 Hyperglycemia

Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions ]. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.

Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with ALIQOPA following adequate glucose control and should be monitored closely.

Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia [see Dosage and Administration ].

 Hypertension

Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions ]. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension [see Dosage and Administration ].

 Non-Infectious Pneumonitis

Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions ]. Withhold ALIQOPA and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis [see Dosage and Administration ].

 Neutropenia

Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3% [see Adverse Reactions ]. Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia [see Dosage and Administration ].

 Severe Cutaneous Reactions

Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy, respectively [see Adverse Reactions ]. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of severe cutaneous reactions [see Dosage and Administration ].

 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose [see Use in Specific Populations and Clinical Pharmacology ].

 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in the general patient population.

The safety data reflect exposure to ALIQOPA in 168 adults with follicular lymphoma and other hematologic malignancies treated with ALIQOPA 60 mg or 0.8 mg/kg equivalent in clinical trials. The median duration of treatment was 22 weeks (range 1 to 206 weeks).

Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). The most common adverse reactions (≥20%) were hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia.

Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most common reasons for dose reduction were hyperglycemia (7%), neutropenia (5%), and hypertension (5%). The most common reasons for drug discontinuation were pneumonitis (2%) and hyperglycemia (2%).

Table 2 provides the adverse reactions occurring in at least 10% of patients receiving ALIQOPA monotherapy, and Table 3 provides the treatment-emergent laboratory abnormalities in ≥20% of patients and ≥4% of Grade ≥3 treated with ALIQOPA.

Additional adverse drug reactions reported at a frequency of <10% in patients with follicular lymphoma and other hematologic malignancies include pneumonitis (9%), mucosal inflammation (8%), and paresthesia and dysesthesia (7%).

*Denominator for each laboratory parameter may vary based on number of patients with specific numeric laboratory values available.

**NCI-CTCAE v4.03

 Effect of Other Drugs on Copanlisib

Table 4 lists the potential effects of coadministration of ALIQOPA with strong CYP3A inhibitors and inducers.

 Mechanism of Action

Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

 Pharmacodynamics

At 60 mg (or 0.8 mg/kg) of ALIQOPA dose, the elevation of plasma glucose was associated with higher copanlisib exposure.

 Pharmacokinetics

The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of ALIQOPA increase dose-proportionally over 5 to 93 mg (0.08 to 1.55 times the approved recommended dose) absolute dose range and exhibit linear pharmacokinetics (PK). There is no time-dependency and no accumulation in the PK of copanlisib.

The geometric mean (range) steady state copanlisib exposure at 0.8 mg/kg (approximately the approved recommended dose of 60 mg) are 463 (range: 105 to 1670; SD: 584) ng/mL for Cmax and 1570 (range: 536 to 3410; SD: 338) ng.hr/mL for AUC0-25h.

 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with copanlisib.

Copanlisib did not cause genetic damage in in vitro or in vivo assays.

Fertility studies with copanlisib were not conducted; however, adverse findings in male and female reproductive systems were observed in the repeat dose toxicity studies. Findings in the male rats and/or dogs included effects on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Findings in female rats included effects on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus.

 Relapsed Follicular Lymphoma

The efficacy of ALIQOPA was evaluated in a single-arm, multicenter, phase 2 clinical trial (NCT 01660451) CHRONOS-1 in a total of 142 subjects, which included 104 subjects with follicular B-cell non-Hodgkin lymphoma who had relapsed disease following at least two prior treatments. Patients must have received rituximab and an alkylating agent. Baseline patient characteristics are summarized in Table 5. The most common prior systemic therapies were chemotherapy in combination with anti-CD20 immunotherapy (89%), chemotherapy alone (41%), and anti-CD20 immunotherapy alone (37%). In CHRONOS-1, 34% of patients received two prior lines of therapy and 36% received three prior lines of therapy.

*Refractory: No response or progression of disease within six months of last treatment.

One hundred forty-two patients received 60 mg ALIQOPA; 130 patients received fixed dose 60 mg ALIQOPA and 12 patients received 0.8 mg/kg equivalent ALIQOPA administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Treatment continued until disease progression or unacceptable toxicity. Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. Efficacy based on overall response rate (ORR) was assessed by an Independent Review Committee. Efficacy results from CHRONOS-1 are summarized in Table 6.

ORR = overall response rate; CI = confidence interval; CR = complete response;

PR = partial response; DOR = duration of response

*Kaplan-Meier estimate

The median time to response was 1.7 months (range 1.3 to 9.7 months).