Summary Basis of Decision for Aloxi ®

The Canadian regulatory decision on the clinical pharmacology studies, including a thorough QTc study, was based on Health Canada's review of the detailed FDA review reports, with reference made to the data filed in Canada as necessary.

The Canadian regulatory decision on the clinical efficacy and safety of Aloxi was based on a critical assessment of the Canadian data package. The foreign reviews completed by the EMA and FDA were used as a reference.

3.3.1 Pharmacodynamics

Information to support market authorization for two Aloxi clinical formulations (IV injection and oral capsules) was submitted for this New Drug Submission (NDS). Both formulations were tested in healthy subjects and patients, mostly as a single-dose. Repeat dosing [once daily for 3 consecutive days in healthy subjects and once every other day for three doses (Days 1, 3, 5) in patients] was tested with the IV formulation only.

Palonosetron was shown to have the potential to prolong the QTc interval based on in vitro non-clinical studies. In addition, a thorough QT study revealed dose-dependent increases in the maximum change of QTcI interval (QT interval corrected individually) from baseline and the numbers of patients with ∆QTcI of 30-60 ms in three palonosetron dose groups, although the maximum ∆QTcI values remained below those of the positive control (400 mg moxifloxacin). Further, cases of QTc prolongation were reported only in palonosetron arms in the active controlled Phase III pivotal studies, although palonosetron did not induce clinically relevant prolongation of the QTc interval at any dose level tested. Finally, 5-HT₃ antagonists are known to cause QTc prolongation. Therefore, information on the potential effect of palonosetron on the QTc interval was recommended to be included in the Aloxi Product Monograph based on the increased risk: in patients who have or are likely to develop prolongation of QT interval for example (e.g.) congenital QT Syndrome, electrolyte imbalance) and/or concomitant use of Aloxi with medicinal products that are associated with QTc prolongation.

3.3.2 Pharmacokinetics

Absorption

Following single IV bolus administration to healthy volunteers, plasma palonosetron concentration exhibited a biphasic decline. After an initial rapid decline in plasma, marked increases were frequently observed at 2-4 hours after dosing, suggesting enterohepatic recirculation of palonosetron. In some subjects, the secondary peak value was higher than the value of the first peak.

After oral administration, palonosetron was well-absorbed, with an absolute bioavailability of ~97%. Maximum plasma concentrations (C_max) were generally seen within 4-5 hours.

The mean C_max and AUC were generally dose-proportional after both IV and oral dosing (over a dose range of 1-80 μg/kg) in healthy subjects and in patients treated for chemotherapy-induced nausea and vomiting (CINV). The C_max and AUC from zero to infinity (AUC_0-∞) values showed considerable variation between subjects. The systemic exposure to palonosetron in terms of AUC was higher in cancer patients by 30% than in healthy subjects, based on a cross-study comparison.

Palonosetron administered at 0.25 mg IV bolus daily for three consecutive days resulted in a 2.1-fold accumulation in healthy subjects. Similarly, palonosetron administered at 0.25 mg IV bolus over 30 seconds on Days 1, 3, and 5 resulted in a 1.42-fold accumulation in cancer patients.

Absorption of oral palonosetron capsules was not affected by a standard high-fat meal and, therefore, oral palonosetron can be taken with or without food.

Distribution

Palonosetron distributed extensively in the body as suggested by a large mean apparent volume of distribution of ~8.3 L/kg. Protein binding in human plasma was constant over the concentration range of 5-412 ng/mL, with an average of 62%. Clearance and volume of distribution parameters after oral administration were similar to those after IV administration.

Metabolism

In vitro studies suggested that metabolism of palonosetron is mediated primarily via cytochrome P450 enzyme (CYP) 2D6, followed by CYP3A4 and CYP1A2. The major metabolites after IV administration were an N-oxide metabolite (M9; ~12.5% of the administered dose) and a hydroxy metabolite (M4; ~10.9% of the administered dose).

Excretion

Palonosetron was eliminated unchanged through renal excretion and through metabolic pathways mediated via multiple CYP isozymes. Following single IV administration of [¹⁴C] palonosetron hydrochloride at 10 μg/kg, renal clearance of unchanged drug amounted to 42% of the total clearance while ~50% of the administered dose was metabolized; ~80% of the dose was recovered within 144 hours in the urine. The mean apparent terminal half-life based on a Phase I study was ~37.4 hours. Estimates of renal clearance after oral dosing ranged from 4.06 to 6.29 L/hour.

Special Populations

Age, gender, and race were not found to significantly affect the PK of palonosetron.

Renal Insufficiency

The mean values of the primary PK parameters for palonosetron in patients with mild to moderate renal impairment were similar to those of healthy subjects. In patients with severe renal impairment, the mean AUC from zero to time (t) (AUC_0-t) increased by approximately 50% compared with healthy subjects and some patients had extended terminal half-lives (115-300 hours). However, no dosage adjustment is recommended for patients with any degree of renal impairment.

Hepatic Insufficiency

The mean AUC of palonosetron was not significantly affected in patients with various degrees of hepatic impairment following a single dose of intravenous palonosetron, while the systemic exposure of one metabolite, M9, was significantly reduced in patients with moderate or severe hepatic impairment. Although the apparent terminal half-life of palonosetron was prolonged by ~50% in patients with moderate and severe hepatic impairment, dosage adjustment is not necessary as palonosetron will be administered as a single dose in the clinical setting.

Drug-Drug Interactions

In vitro studies indicated that palonosetron does not inhibit or induce the activity of CYP isozymes at therapeutic concentrations. In vivo pharmacokinetic studies showed that single-dose palonosetron IV did not interact with metoclopramide dosed orally to steady-state, IV dexamethasone, or oral aprepitant, while concomitant administration of an antacid had no effect on the oral absorption or pharmacokinetics of oral palonosetron.

Bioequivalence

A single-dose, two-way crossover comparative bioavailability study was conducted in healthy adult subjects under fasting conditions to compare the clinical trial formulation and commercial formulation of oral palonosetron (0.5 mg). The data provided demonstrates that the clinical trial formulation and commercial formulation of Aloxi 0.5 mg capsules are bioequivalent based on Health Canada's bioequivalence standards.

3.3.3 Clinical Efficacy

Aloxi Injection for Moderately Emetogenic Chemotherapy

Evidence for the efficacy of IV palonosetron in patients receiving an initial course of moderately emetogenic chemotherapy (MEC) was provided in two pivotal studies (PALO-99-03 and PALO-99-04).

The two pivotal studies involved 1,132 patients and compared a single IV dose of Aloxi (0.25 mg, 0.75 mg) with a single IV dose of either ondansetron (32 mg) or dolasetron (100 mg) given 30 minutes prior to MEC including carboplatin, cisplatin ≤50 mg/m²), cyclophosphamide <1,500 mg/m², doxorubicin >25 mg/m², epirubicin, irinotecan, or methotrexate. Concomitant corticosteroids were not administered prophylactically in study PALO-99-03 and were used by only 4-6% of patients in study PALO-99-04. Thus, the effect of concomitant corticosteroids could not be evaluated in either study.

The primary endpoint was complete response [(CR); no emetic episode and no rescue medication] within 24 hours following chemotherapy (acute phase). Secondary endpoints included complete control [(CC); defined as CR and no more than mild nausea], number of emetic episodes, time to first emetic episode, time to first administration of rescue medication, time to treatment failure, severity and intensity of nausea, patient global satisfaction with anti-emetic therapy, and quality of life.

Non-inferiority of both palonosetron 0.25 mg and 0.75 mg to ondansetron 32 mg or to 100 mg dolasetron was demonstrated in both studies for the prevention of MEC-induced nausea and vomiting based on CR during the first 24 hours after chemotherapy. Efficacy was also supported by non-inferiority for all secondary efficacy endpoints within 0-24 hours after chemotherapy.

Because ondansetron and dolasetron are indicated for the prevention of the acute phase of emesis and not the delayed phase (24-120 hours), superiority over the comparators is needed to establish efficacy for palonosetron during the delayed phase. During the delayed phase and overall (0-120 hours), superiority in CR rates, CC rates and No Nausea rates was demonstrated in the 0.25 mg IV palonosetron group in both pivotal studies. Superiority in CR rates, CC rates, and No Nausea rates for the 0.75 mg palonosetron group was demonstrated in study PALO-99-04 but not in study PALO-99-03. Therefore, 0.25 mg IV palonosetron is considered effective for the prevention of acute and delayed nausea and vomiting associated with an initial course of MEC.

Aloxi Injection for Highly Emetogenic Chemotherapy

Evidence for the efficacy of IV palonosetron in patients receiving an initial course of highly emetogenic chemotherapy (HEC) was provided in two studies: pivotal study PALO-99-05 and a supportive dose-ranging study (Study 2330).

Study PALO-99-05 was a Phase III, double-blind, three-arm randomized study involving 667 patients and compared a single IV dose of Aloxi (0.25 mg, 0.75 mg) with single IV dose of ondansetron (32 mg) given 30 minutes prior to HEC comprising cisplatin ≥60 mg/m², cyclophosphamide, or dacarbazine. Dexamethasone, or in the event of a shortage, methylprednisolone, was co-administered prophylactically before chemotherapy at the discretion of the investigators, and 67% of patients were co-administered these corticosteroids.

Non-inferiority of both palonosetron doses to ondansetron 32 mg was demonstrated for the CR rates during the first 24 hours after chemotherapy. The results from the per protocol cohort were consistent with the intent-to-treat analysis. Non-inferiority of both palonosetron doses to ondansetron with regard to CR rates was also shown for all additional time periods on cumulative and daily results. However, superiority was not demonstrated by CR, CC rates or other secondary endpoints during the delayed phase (24-120 hours) or overall (0-120 hours).

Subgroup analysis suggested that prophylactic corticosteroid use was necessary to maintain the non-inferior efficacy of 0.25 mg palonosetron with ondansetron during the acute phase as assessed by the CR rates, although it is noted that the study was not powered to demonstrate non-inferiority in these individual subgroups. Thus, it is indicated in the Product Monograph that efficacy of Aloxi in the prevention of acute nausea and vomiting induced by HEC was demonstrated mainly in patients who were co-administered prophylactic corticosteroids.

The efficacy results in patients administered HEC in the Phase III study were supported by the results from the Phase II dose-ranging study. Thus, 0.25 mg IV palonosetron is considered effective for the prevention of acute nausea and vomiting associated with an initial course of HEC.

Aloxi Capsules for Moderately Emetogenic Chemotherapy

Evidence for the efficacy of oral palonosetron in patients receiving an initial course of MEC was provided in one pivotal study (PALO-03-13).

PALO-03-13 was a multicentre, randomized, double-blind, active-control clinical study of 635 patients receiving MEC comprising cyclophosphamide <1.500 mg/², doxorubicin, carboplatin, epirubicin, or idarubicin. A single dose of 0.25 mg, 0.5 mg, or 0.75 mg oral Aloxi capsules administered one hour prior to MEC was compared with a single dose of 0.25 mg Aloxi IV administered 30 minutes prior to chemotherapy. In each treatment group, patients were further randomized to receive either dexamethasone or placebo.

The primary efficacy endpoint was CR during the first 24 hours after the start of chemotherapy. Secondary efficacy endpoints included CR in the delayed phase, CC, number of emetic episodes, time to first emetic episode, time to first administration of rescue medication, time to treatment failure, severity and intensity of nausea, patient global satisfaction with anti-emetic therapy, and quality of life. Efficacy was based on non-inferiority of oral palonosetron compared with the IV formulation.

Non-inferiority of all three oral palonosetron doses to palonosetron 0.25 mg IV was demonstrated by CR rates during the first 24 hours after chemotherapy. However, no dose dependence was observed when comparing the three oral groups. The CR rates during the acute phase were comparable between the three oral palonosetron treatment groups, and the highest rate was found in the 0.50 mg group. Further, non-inferiority of CR rates of the three palonosetron doses to palonosetron 0.25 mg IV was not shown during the delayed phase. These results were consistent with those of CC rates and other secondary endpoints. Finally, markedly improved efficacy (CR rates ~20% higher) was observed when oral or IV palonosetron was co-administered with prophylactic corticosteroids and these results are included in the Product Monograph. Therefore, 0.50 mg oral palonosetron is considered effective for the prevention of acute nausea and vomiting associated with an initial course of MEC.

3.3.4 Clinical Safety

Aloxi Injection

In the Phase I and Phase II studies, the most frequently reported AEs occurring in ≥5% of patients who received palonosetron were: headache; constipation; fever; abdominal pain; diarrhoea; itching (pruritus); pain; asthenia; and insomnia. In addition, dizziness and anorexia were reported in >5% of the patients who received ≥30 μg/kg of palonosetron, and back pain was reported in >5% of patients who received 10-20 μg/kg of palonosetron. An increase in liver enzymes, tachycardia, bradycardia, abnormal electrocardiograms, chest pain (angina), hypotension, and hypertension were also reported.

In the Phase III clinical studies, 1,374 patients received IV palonosetron, including 605 patients receiving a single dose of 0.25 mg. Most of the common adverse drug reactions reported were associated with gastrointestinal, nervous system, and general disorders. Headache, constipation, diarrhoea, fatigue, and musculoskeletal pain were among the most common AEs observed.

Most AEs reported were of mild intensity and considered unrelated or unlikely to be related to palonosetron treatment. Treatment-related AEs were reported in ~20% of patients overall in the three pivotal studies. The most frequently reported treatment-related AEs for 0.25 mg IV palonosetron were headache and constipation. Serious AEs (SAEs) were uncommon and all SAEs except one (convulsion reported in a patient treated with concomitant dexamethasone in the repeat-course study) were assessed as unrelated or unlikely to be related to palonosetron administration. There were no deaths judged to be related to the study drug.

Overall, there were no consistent clinically significant safety concerns associated with laboratory parameters or vital signs. However, more clinically relevant abnormal ECG findings including cases of mild QTc prolongation were reported in the palonosetron groups compared with the ondansetron or dolasetron group in the pivotal studies.

Aloxi Capsules

The safety database for oral palonosetron included data from 4 studies: two Phase II studies (Studies 2332 and PALO-04-03); and two Phase III studies (Studies PALO-03-13 and PALO-03-14). A total of 1,061 patients were enrolled in these four studies, 182 of whom received 0.50 mg oral palonosetron.

Overall, gastrointestinal disorders were the most frequently reported AEs (19.7%), followed by nervous system disorders (18.2%). The majority of the AEs reported were of mild intensity. Less than 8% of AEs were assessed as severe.

The majority of AEs were not considered related to study medication. Drug-related AEs were reported with similar frequencies in the patients in the three oral palonosetron groups (7.0%, 8.1%, and 7.6%, respectively), while the percentage of patients with drug-related AEs in the IV palonosetron group was approximately twice as high (16.0%). The most common drug-related AEs were headache and constipation.

In the pivotal Phase III study (PALO-03-13), 32 SAEs were reported by 17 patients (2.7%) and one SAE (atrioventricular block second degree) was considered as related to palonosetron. Anaemia, chest pain and dyspnoea were the only SAEs reported for more than one patient and seen in more than one treatment group. No deaths were judged to be related to the study drug. When ECGs recorded at ~3 hours post dose were compared with baseline ECG values, the incidence of patients with abnormal ECGs slightly increased and the mean QTc duration increased (QTcB: 4-6 ms) in all four treatment groups. In the oral 0.5 mg group, 26% of the patients had QTcB increases from 30-60 ms but none had an increases of QTcB >60 ms.

Aloxi Injection and Aloxi Capsules

Palonosetron (IV and oral at a supratherapeutic dose) was studied in two open-label, safety studies during repeat courses (up to 9 and 4 cycles; median: 2 and 3 cycles for IV and oral, respectively) of chemotherapy (MEC or HEC). The overall reported safety profiles of palonosetron were similar among all cycles.

A Phase I study in 12 healthy subjects who received IV palonosetron 0.25 mg once daily for three consecutive days showed a 2.1-fold accumulation of systemic exposure (ratio of Day 3 to Day 1 AUC_0-24 hours). In another repeat-dose study, palonosetron 0.25 mg IV was administered on Days 1, 3 and 5 to male cancer patients receiving 20 mg/m² cisplatin on Days 1 to 5. This resulted in a 1.4-fold accumulation (ratio of Day 5 to Day 1 AUC_0-t). There is limited safety information regarding repeat dosing of Aloxi. Daily dosing of palonosetron in the second study produced a pharmacokinetic profile consistent with the long plasma elimination half-life of palonosetron of ~40 hours.

There are no clinical data on the outcome of palonosetron exposure during pregnancy and non-clinical reproductive studies revealed low foetal weight, reduced ossification and maternal toxicity. Palonosetron should be used during pregnancy only if clearly needed.

It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions and tumorigenicity in nursing infants, the use of palonosetron during lactation is not recommended.

There is no known antidote to palonosetron and overdosage should be managed with supportive care. The highest dose of palonosetron administered in any of the clinical studies was 90 μg/kg, which is ~12 times the recommended oral dose of 0.5 mg. Adverse events in this high-dose group were similar to those of the lower doses used in these studies.