Approval date: XXXX XXXX, XXXX
Date of modification.
Aletinib hydrochloride capsule instructions
Please read the instructions carefully and use under the guidance of a physician
[Drug Name].
General
Use
Name：Aletinib Hydrochloride Capsules
Commercial
Product
Name: Alecensa®,
English trade name Alecensa®
English
Language
Name: Alectinib Hydrochloride Capsules
Hanyu Pinyin：Yansuan Alaitini Jiaonang
Ingredients
The main active ingredient of this product is Alaitini.
Chemical name: 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)G piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride.
Chemical structure formula.
Molecular
Sub
Formula: C30H35ClN4O2 (hydrochloride)
molecule
molecule
Amount: 519.08 (hydrochloride)
Excipients: lactose monohydrate, hydroxypropyl cellulose, sodium dodecyl sulfate, magnesium stearate and calcium carboxymethyl cellulose. The capsule shell contains hydroxypropyl methylcellulose, carrageenan, potassium chloride, titanium dioxide, corn starch and Brazilian carnauba wax. The printing ink contains iron oxide red (E172), iron oxide yellow (E172), FD&C blue 2 aluminum precipitate (E132), Brazilian carnauba wax, white worm gum, glycerol monooleate, 1-butanol and anhydrous ethanol.
Properties
150mg white hard capsule with the word “ALE” printed in black ink on the capsule cap and “150 mg” printed in black ink on the capsule body.
Indications
This product is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who are positive for mesenchymal lymphoma kinase (ALK) as a single agent.
Specification
150 mg (equivalent to 161.33 mg of aletinib hydrochloride in aletinib form).
Dosage]
Patient selection
This product should be used in a healthcare facility with experience in its use and under the direction of a specific technical professional. A positive ALK assessment confirmed by a well-validated assay must be obtained prior to administration of this product.
Recommended Dosage
The hard capsule should be taken with a meal, swallowed whole, and should not be opened or dissolved.
The recommended dose of this product is 600 mg (4 capsules of 150 mg) administered orally twice daily (total daily dose of 1200 mg) (see [Pharmacokinetics]).
Duration of treatment
Patients are advised to receive this product until disease progression or intolerable toxicity occurs.
Delayed or Missed Doses
Patients who miss a scheduled dose of this product should make up that dose unless it is less than 6 hours before the next dose. Patients who experience vomiting after taking the drug should take the next dose of the drug at the scheduled time.
Dose Adjustment
If adverse events occur during treatment, it may be necessary to temporarily interrupt dosing, reduce the dose, or discontinue treatment with this product. The dose of this product should be reduced gradually by 150 mg per dose reduction, as tolerated by the patient. If the patient cannot tolerate the 300 mg twice-daily dose, treatment should be permanently discontinued.
Table 1 shows the general dose adjustment recommendations for this product.
Table 1 Dose reduction regimen
Dose reduction regimen Dose level Standard dose 600 mg twice daily First dose reduction 450 mg twice daily Second dose reduction 300 mg twice daily
Table 2 Dose adjustment recommendations for specific adverse drug reactions (see [Precautions] and [Adverse Reactions])
Adverse Reaction Classification (per CTCAE) Dose Adjustment for Interstitial Lung Disease (ILD)/Non-Infectious Pneumonia (all grades) Immediately discontinue treatment with this product, or permanently if no other underlying cause of ILD/Non-Infectious Pneumonia is identified. Grade ≥3 ALT or AST elevation (>5×ULN) with total bilirubin ≤2×ULN Suspend therapy until return to baseline levels or ≤Grade 1 (≤3×ULN) and continue treatment with reduced dose according to Table 1 protocol. Suspend treatment for grade ≥2 ALT or AST elevation (>3×ULN) with total bilirubin elevation >2×ULN, without cholestasis or hemolysis Permanently suspend treatment for total bilirubin elevation >3×ULN until it returns to baseline or ≤1.5xULN, then continue treatment with reduced dose according to the regimen in Table 1 Grade 3 renal impairment Suspend treatment for grade 3 renal impairment until serum creatinine returns to ≤1.5 xULN, then continue treatment at reduced doses according to the regimen in Table 1. grade 4 renal impairment permanently discontinue this product. grade 2 or 3 bradycardiaa (symptomatic, potentially severe and clinically significant, requiring clinical intervention)
Suspend therapy until bradycardia returns to ≤ grade 1 (asymptomatic) or heart rate ≥ 60 bpm.
Evaluate the combination of medications known to trigger bradycardia and antihypertensive agents.
If a combination medication causing bradycardia is identified and discontinued or dose adjusted, resume dosing at the pre-suspension dose after the patient’s bradycardia has returned to ≤ grade 1 (asymptomatic) or a heart rate ≥ 60 bpm.
If no comorbid medication causing bradycardia is identified, or if the dose of such comorbid medication cannot be discontinued or adjusted, continue treatment at a reduced dose according to Table 1 after the patient’s bradycardia has returned to Grade 1 (asymptomatic) or a heart rate of ≥60 bpm. Grade 4 bradycardiaa (life-threatening, requiring urgent intervention) If no comorbid medication causing bradycardia is identified, permanently discontinue treatment with this product.
If a combination of drugs causing bradycardia is identified and discontinued or dose adjusted, continue treatment at a reduced dose according to Table 1 after the patient’s bradycardia returns to ≤ grade 1 (asymptomatic) or a heart rate ≥ 60 bpm, and monitor closely according to clinical indications. If bradycardia recurs, permanently discontinue treatment with a CPK elevation >5 x ULN until it returns to baseline or ≤2.5 x ULN, then resume dosing at the pre-suspension dose with a CPK elevation >10 x ULN or a second CPK elevation >5 x ULN until it returns to baseline or ≤2.5 x ULN. ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; ULN = upper limit of normal
; CTCAE = National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
a Heart rate less than 60 beats per minute (bpm)
Dosing Instructions for Special Populations
Children: The safety and efficacy of this product has not been studied for use in children and adolescents (<18 years of age).
Elderly: No dose adjustment is required for patients aged ≥65 years receiving this product.
Renal Impairment: No dose adjustment is required for patients with mild or moderate renal impairment. This product has not been studied in patients with severe renal impairment. However, no dose adjustment is required in patients with severe renal impairment because of negligible excretion of aletinib through the kidneys (see [Precautions] and [Pharmacokinetics])
.
Hepatic impairment: No dose adjustment is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The dose for patients with severe (Child-Pugh Class C) hepatic impairment should be 450 mg administered orally twice daily (total daily dose of 900 mg) (see [Precautions] and [Pharmacokinetics]).
[Adverse Reactions].
This instruction describes the adverse reactions that may be caused by aletinib and their approximate incidence as observed in clinical trials and post-marketing applications. Because clinical trials are conducted under a variety of different conditions, the incidence of adverse reactions observed in one clinical trial cannot be directly compared with the incidence of adverse reactions observed in another clinical trial and may not reflect the actual incidence in clinical practice.
Adverse reactions in clinical trials
Approximately 928 patients were treated with aletinib in clinical trials, of which 203 patients were treated with this product in a blinded state. In the pivotal phase II clinical trials (NP28761, NP28673), the safety of 253 patients with ALK-positive non-small cell lung cancer treated with aletinib 600 mg twice daily was evaluated with a median exposure time of 11 months (range: 0-35 months). In the phase III clinical trial BO28984, the safety of 152 patients with ALK-positive non-small cell lung cancer treated with aletinib 600 mg twice daily was evaluated with a median exposure time of 17.9 months.
The most common adverse drug reactions (≥20%) included constipation (36%), edema (34%, including peripheral edema, generalized edema, eyelid edema, and periorbital edema), myalgia (31%, including myalgia and musculoskeletal pain), nausea (22%), elevated bilirubin (21%, including elevated blood bilirubin, hyperbilirubinemia, and elevated conjugated bilirubin), anemia (20%, including anemia and decreased hemoglobin) and rash (20%, including rash, maculopapular rash, acneiform dermatitis, erythema, generalized rash, papulopapular rash, pruritic rash, and maculopapular rash).
Table 3 summarizes the adverse drug reactions (ADRs) that occurred in patients treated with this product in Phase II clinical trials (NP28761, NP28673) and in Phase III clinical trial BO28984. Adverse drug reactions from clinical trials are presented according to the MedDRA system organ classification. The frequency of each adverse drug reaction was defined by the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); occasional (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); and very rare (< 1/10000). Within each system organ classification, adverse reactions are presented in descending order of frequency of occurrence.
Table 3 Adverse drug reactions occurring in patients treated with aletinib in phase II clinical trials (NP28761, NP28673) and phase III clinical trials (BO28984)
Adverse reactions (MedDRA) Arletinib
N=253 (NP28761, NP28673) or N=152 (BO28984)
Systemic organ classification All levels (%) Level 3 – 4 (%) Frequency category
(all levels) Gastrointestinal system disorders constipation 36 0 very common nausea 22 0.7 # very common
Diarrhea 18 1.2 Very common Vomiting 13 0.4 Very common Stomatitis #13.3 #0# Very common Systemic diseases and administration site reactions Edema 234 0.8 Very common Musculoskeletal and connective tissue disorders
Myalgia 331 1.2 Very common elevated blood creatine phosphokinase
13 3.6 Very common skin and subcutaneous tissue disorders rash 4200.7# Very common
Photosensitivity reactions 12 0.7#Very commonNeurological disordersTaste disorders #53.3#0.7#Very commonHepatobiliary disordersBilirubin elevation 6
21#3.3#Very common Elevated AST
16 5.3#Very common elevated ALT
15#4.6#Very common drug-related liver injury 70.8 0.8 Occasional blood and lymphatic system disorders anemia 820#4.6#Very common eye organ disorders visual disturbances 912 0 Very common heart organ disorders bradycardia 1011#
0 Very common all types of screening weight gain#9.9#0.7# Common renal and urinary system disorders elevated creatinine7.9#1.3#* Common acute kidney injury#2.6#2.6#* Common respiratory, thoracic and mediastinal disorders interstitial lung disease/non-infectious pneumonia1.3#0.4 Common*
Includes one grade 5 event
# Events and/or incidences reported in clinical trial BO28984; N=152 patients treated with this product; (Note: others not marked with # are events and/or incidences reported in clinical trials NP28761 and NP28673; N=253 patients treated with this product). For the same adverse reaction, listed in the table are the higher values from BO28984 or NP28761 and NP28673.
1
Including cases of stomatitis and mouth ulcers
2
Includes cases of peripheral edema, edema, generalized edema, eyelid edema, and periorbital edema
3 Including myalgia and musculoskeletal pain cases
4 Including cases of rash, maculopapular rash, acneiform dermatitis, erythema, generalized rash, papulopapular rash, pruritic rash, and maculopapular rash
5
Including cases of taste disorder and hypertaste
6
Includes cases of elevated blood bilirubin, hyperbilirubinemia and elevated conjugated bilirubin
7 Includes one patient who reported MedDRA term drug-related liver injury and one patient who reported grade 4 AST and ALT elevations and had drug-related liver injury confirmed by liver biopsy.
8
Includes cases of anemia and decreased hemoglobin
9
Includes cases of blurred vision, visual impairment, miosis, decreased visual acuity, visual fatigue and diplopia
10
Including cases of bradycardia and sinus bradycardia
Further information on specific adverse reactions
The safety profile of aletinib in the pivotal Phase III trial BO28984 was generally consistent with the Phase II trials NP28761 and NP28673.
Interstitial Lung Disease (ILD)/Non-Infectious Pneumonia
Severe interstitial lung disease/non-infectious pneumonia was observed in patients treated with aletinib in clinical trials. In three clinical trials (NP28761, NP28673, BO28984), one grade 3 interstitial lung disease event occurred in 1 patient (0.2%) of 405 patients treated with aletinib and resulted in patient withdrawal from treatment. In the phase III clinical trial BO28984, no grade 3 or 4 interstitial lung disease/non-infectious pneumonia occurred in patients treated with this product, and the incidence was 2.0% in patients treated with crizotinib. No fatal cases of interstitial lung disease have been reported in all clinical trials. Patients should be monitored for the development of pulmonary symptoms suggestive of non-infectious pneumonia (see [DOSAGE] and [PRECAUTIONS]).
Hepatotoxicity
In three clinical trials (NP28761, NP28673, BO28984), adverse reactions of elevated AST and ALT were reported in 15% and 14% of patients treated with aletinib, respectively. The majority of events were grade 1 and 2, with 3.7% of patients each reporting grade ≥3 AST or ALT elevation events. These events generally occurred within the first 3 months of treatment, were usually transient, and recovered after suspension of aletinib therapy (1.5% and 3.0% of patients, respectively) or dose reduction (2.2% and 1.2%, respectively). The drug was discontinued in 1.2% and 1.5% of patients due to elevated AST and elevated ALT, respectively. In three clinical trials, two patients who experienced grade 3-4 AST/ALT elevations had drug-related liver injury confirmed by liver biopsy, and one patient experienced a grade 4 drug-related liver injury adverse event; two of these cases withdrew from treatment with alectinib. 5% of patients treated with alectinib in the phase III clinical trial BO28984 each experienced grade 3 or 4 ALT or AST elevation, and 15% and 11% of patients receiving crizotinib, respectively.
In three clinical trials (NP28761, NP28673, BO28984), 18% of patients treated with aletinib reported adverse reactions of elevated bilirubin. Most events were grade 1 and 2; grade 3 events were reported in 3.2% of patients. These events generally occurred within the first 3 months of treatment, were usually transient, and most recovered after dose adjustment. Dose adjustment due to elevated bilirubin was reported in 5.2% of patients and withdrawal from aletinib treatment due to elevated bilirubin was reported in 1.5% of patients. In the phase III clinical trial BO28984, the incidence of grade 3 or 4 bilirubin elevations was 3.3% in patients treated with aletinib and no such events occurred in patients treated with crizotinib.
In clinical trials of this product, 1 patient (0.2%) had a concurrent ALT or AST elevation ≥3 x ULN and total bilirubin elevation ≥2 x ULN with normal alkaline phosphatase.
Liver function (including ALT, AST and total bilirubin) should be monitored (see [Precautions]) and dose adjusted (see [Dosage]).
Bradycardia
In three clinical trials (NP28761, NP28673, BO28984), grade 1 or 2 bradycardia was reported in 8.9% of patients treated with aletinib, and no patients experienced a grade ³3 event. Of the 365 patients treated with aletinib who had post-dose heart rate data, 66 patients (18%) had heart rates below 50 beats/min. In the phase III clinical trial BO28984, 15% of patients treated with aletinib had a heart rate of less than 50 beats/min after administration, compared with 20% of patients receiving crizotinib. Patients presenting with symptomatic bradycardia should be managed according to [DOSAGE] and [PRECAUTIONS]. No patients have discontinued the drug because of bradycardia.
Severe myalgia and elevated CPK
In three clinical trials (NP28761, NP28673, BO28984), 28% of patients treated with aletinib reported myalgia, including myalgic events (22%) and musculoskeletal pain (7.4%). Most events were grade 1 or 2, with grade 3 events occurring in 3 patients (0.7%). Only 2 patients (0.5%) required dose adjustment of aletinib due to adverse events; no patients withdrew from aletinib therapy because of myalgia events. 43% of 362 patients with CPK laboratory data had CPK elevations, and the incidence of grade 3 CPK elevations was 3.7%, with a median time to grade 3 CPK elevation of 14 days. 3.2% of patients had dose adjustments due to CPK dose adjustment due to CPK elevation; no patients withdrew from aletinib treatment due to CPK elevation. In the pivotal phase III trial BO28984, no severe myalgia was reported; grade 3 CPK elevation was reported in 2.6% of patients treated with aletinib and 1.3% of patients treated with crizotinib; the median time to onset of grade 3 CPK elevation was 27.5 days and 369 days, respectively.
Gastrointestinal reactions
The most frequently reported gastrointestinal reactions were constipation (35%), nausea (19%), diarrhea (16%), and vomiting (11%). Most events were mild or moderate in severity; Grade 3 events reported included diarrhea (0.7%), nausea (0.5%), and vomiting (0.2%). These events did not result in patient withdrawal from aletinib treatment. In each trial (NP28761, NP28673, BO28984), the median time to onset of constipation, nausea, diarrhea, and/or vomiting events was 21 days. The frequency of these events decreased after completion of Month 1 of treatment. In the phase III clinical trial BO28984, grade 4 nausea events occurred in 1 patient (0.2%) in the aletinib arm, and the incidence of grade 3 and 4 nausea, vomiting and diarrhea events in the crizotinib arm was 3.3%, 3.3% and 2.0%, respectively. Laboratory test abnormalities
Table 4 summarizes the treatment-emergent laboratory test abnormalities that occurred in patients treated with this product in the phase II clinical trials (NP28761, NP28673) and in the phase III clinical trial BO28984.
Table 4 Changes in significant laboratory test abnormalities that occurred during treatment with this product
Parameters aletinib
N= 250* or N=152# All grades (%) Grade 3 – 4 (%) ° Biochemistry Elevated blood creatinine** 38#3.4# Elevated AST
53*6.2# ALT elevated
40#6.1# Elevated blood creatine phosphokinase
46#5.0# Elevated blood bilirubin
53#5.5# Hematology Hemoglobin decreased 62#6.8# AST – aspartate aminotransferase, ALT – alanine aminotransferase
Note: Abnormal laboratory tests are based on the normal range of values for NCI CTCAE.
*
Incidence reported in clinical studies NP28761 and NP28673, 3 patients were not included in the analysis due to lack of baseline laboratory test values; for creatine phosphokinase, N=219.
**
Only patients with elevated creatinine according to the ULN definition (CTCAE classification) were included
# Incidence reported in clinical trial BO28984; patients with missing baseline values and/or missing post-baseline laboratory assessments have been excluded from these analyses; for blood creatinine, ALT and hemoglobin, N=147; for AST, N=145; for blood bilirubin, N=146
°
No grade 5 laboratory test abnormalities were reported.
Post-marketing experience
Post-marketing adverse drug reactions with elevated alkaline phosphatase occurring after treatment with aletinib have been reported. Cases of elevated alkaline phosphatase have been reported in clinical trials (7.5% incidence in patients treated with aletinib in pivotal phase II clinical trials NP28761 and NP28673).
[Contraindicated].
Contraindicated in patients with known hypersensitivity to aletinib or any of the excipients of this product.
[Precautions].
Interstitial lung disease (ILD)/non-infectious pneumonia
Cases of interstitial lung disease/non-infectious pneumonia have been reported in clinical trials of this product (see [Adverse Reactions]). Patients should be monitored for the development of pulmonary symptoms suggestive of non-infectious pneumonia. Patients with a confirmed diagnosis of interstitial lung disease/non-infectious pneumonia should discontinue this product immediately and permanently if no other underlying cause of interstitial lung disease/non-infectious pneumonia is identified (see [DOSAGE]).
Hepatotoxicity
Patients in the pivotal clinical trial of this product experienced elevations of ALT and AST >5 x upper limit of normal (ULN) and bilirubin >3 x ULN (see [Adverse Reactions]). Most events occurred within 3 months of initial treatment. In the pivotal clinical trial, pharmacologic liver injury occurred in 3 patients with grade 3-4 AST/ALT elevations. In the clinical trial, 1 treated patient had a concurrent ALT or AST elevation ≥ 3 x ULN and total bilirubin elevation ≥ 2 x ULN with normal alkaline phosphatase.
Liver function, including ALT, AST, and total bilirubin, should be monitored at baseline, biweekly for the initial 3 months of treatment, and periodically thereafter, as these events may occur after 3 months of treatment. More frequent monitoring should be performed in patients in whom elevated aminotransferases and bilirubin have occurred. Suspend treatment with this product depending on the severity of the adverse drug reaction, then reduce the dose and continue treatment, or discontinue treatment with this product permanently as described in Table 2 (see [DOSAGE AND ADMINISTRATION]).
Severe Myalgia and Elevated Creatine Phosphokinase (CPK)
Myalgia and musculoskeletal pain, including grade 3 events, were reported in the pivotal clinical trial of this product.
Elevated CPK occurred in patients in pivotal clinical trials of this product, including Grade 3 events. The median time to occurrence of a Grade 3 CPK elevation was 14 days in pivotal Phase II clinical trials (NP28761, NP28673). In the pivotal phase III clinical trial (BO28984), the median time to onset of grade 3 CPK elevation was 27.5 days (see [Adverse Reactions]).
Patients are advised to report any unexplained myalgia, tenderness or weakness. Assess CPK levels biweekly during the first month of treatment and subsequently as needed in the clinic based on patient-reported symptoms. Suspend treatment with this product depending on the severity of CPK elevation and then resume treatment or reduce the dose (see [DOSAGE]).
Impaired Renal Function
In studies NP28761, NP28673, and BO28984, the incidence of grade ≥3 renal impairment was 1.7%, of which 0.5% were lethal events. 3.2% of patients required dose adjustment due to impaired renal function. The median time to grade ≥3 renal impairment was 3.7 months (range, 0.5 to 14.7 months).
If Grade 4 nephrotoxicity occurs, discontinue the product permanently. If Grade 3 nephrotoxicity occurs, discontinue the product until recovery to ≤1.5 × ULN and then resume therapy at the reduced dose (see [DOSAGE AND ADMINISTRATION]).
Bradycardia
Symptomatic bradycardia can occur with this treatment (see [Adverse Reactions]). Heart rate and blood pressure should be monitored according to clinical indications. If asymptomatic bradycardia occurs, no dose adjustment is necessary (see [DOSAGE AND ADMINISTRATION]). If a patient experiences symptomatic bradycardia or a life-threatening event, evaluate the combination of drugs known to cause bradycardia and antihypertensive agents and adjust the dose of this treatment as described in Table 2 (see [DOSAGE AND ADMINISTRATION] and [DRUG INTERACTIONS]).
Photosensitivity
Photosensitivity to sunlight has been reported with aletinib therapy (see [Adverse Reactions]). Patients should be advised to avoid prolonged sun exposure while taking this product and for at least 7 days after treatment has been discontinued. In addition, patients should be advised to use a broad-spectrum sunscreen and lip balm (SPF ≥ 50) that protects against ultraviolet A (UVA)/ultraviolet B (UVB) rays to prevent possible sunburn.
Embryo-Fetal Toxicity
This product may cause fetal harm when administered to a pregnant female. When administered to pregnant rats and rabbits, aletinib produced embryo-fetal toxicity. Female patients of childbearing potential or female partners of childbearing potential of male patients treated with this product must use highly effective methods of contraception during treatment and for at least 3 months after the last dose of this product (see [Use in Pregnant and Lactating Women]).
Drug abuse and drug dependence
None
Ability to drive and operate machinery
This product has a mild effect on the ability to drive and operate machinery. Caution should be exercised when driving or operating machinery because patients may experience symptomatic bradycardia (e.g., syncope, dizziness, hypotension) or visual disturbances while taking this product.
Pregnant and lactating women]
Women of childbearing potential and men
Contraception
Female patients of childbearing potential or female partners of childbearing potential of male patients treated with this product must use a highly effective method of contraception during treatment and for at least 3 months after the last dose of this product.
Pregnant women
Women of childbearing age are advised to use contraception while taking this product. Clinical studies on this product have not been conducted in pregnant women. Depending on the mechanism of action of this product, it may cause fetal harm in pregnant women while taking this product.
If a female patient or the female partner of a male patient treated with this product becomes pregnant while taking this product or within 3 months of the last dose of this product, the physician must be contacted and informed of the potential fetal harm.
Animal Data
In animal studies, aletinib can cause embryo-fetal toxicity (see [Pharmacologic Toxicology]).
Fertility and Delivery
The safety of this product for use during labor and delivery has not been established.
Lactating Women
It is not known whether this product is secreted into human breast milk. Studies have not been conducted to determine the effect of this drug on milk secretion or whether the drug is secreted into human milk. Because many drugs can be secreted into human milk and may potentially harm the infant, nursing women are advised to stop breastfeeding while taking this product.
Pediatric Use]
Safety and efficacy in patients under 18 years of age have not been established.
Geriatric use
See [Dosage] and [Pharmacokinetics].
Drug Interactions]
Effects of aletinib on other drugs
CYP substrates
In vitro studies have shown that neither clinically relevant concentrations of aletinib nor its major active metabolite (M4) inhibit CYP1A2, CYP2B6, CYP2C9, CYP2C19 or CYP2D6. aletinib and M4 have weak time-dependent inhibition of CYP3A4. In vitro studies have shown a potentially weak induction of CYP3A4 and CYP2B6 by clinical concentrations of aletinib.
Results from a clinical drug-drug interaction study in patients with ALK-positive non-small cell lung cancer demonstrated that multiple dosing of aletinib had no effect on exposure to midazolam, a sensitive CYP3A substrate. Therefore, no dose adjustment is required for coadministration with CYP3A substrates.
Although in vitro studies suggest that aletinib is an inhibitor of CYP2C8, physiological pharmacokinetic (PBPK) modeling supports the notion that clinically relevant concentrations of aletinib are unlikely to increase plasma concentrations of CYP2C8 substrates given in combination.
P-gp and BCRP substrates
In vitro, aletinib and M4 are inhibitors of the efflux transport protein P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Therefore, aletinib may increase the plasma concentration of P-gp or BCRP transporter protein substrates given in combination (no more than a 2-fold increase in exposure is expected). Appropriate monitoring is recommended when alectinib is co-administered with therapeutically narrowed P-gp or BCRP substrates (e.g., digoxin, dabigatran, methotrexate).
Effect of other drugs on aletinib
In vitro data suggest that CYP3A4 is the primary enzyme mediating the metabolism of aletinib and its major active metabolite, M4, with CYP3A accounting for 40%-50% of total hepatic metabolism. m4 inhibits ALK in vitro with similar potency and activity to aletinib.
CYP3A inducers
The effect of 600 mg rifampicin (a strong CYP3A inducer) administered orally once daily in multiple consecutive doses versus 600 mg aletinib combined in a single oral dose on total exposure to aletinib and M4 was small (geometric mean ratio [90% confidence interval] with/without combined rifampicin dosing: Cmax: 0.96 [0.88 to 1.05], AUCinf. 0.82 [0.74 to 0.90]). Therefore, no dose adjustment is required when this product is combined with CYP3A inducers.
CYP3A inhibitors
The effect of 400 mg posaconazole (a strong CYP3A inhibitor) administered orally twice daily in multiple consecutive doses in combination with 300 mg aletinib as a single oral dose on total exposure to aletinib and M4 was small (geometric mean ratio [90% confidence interval] with/without posaconazole dosing: Cmax: 0.93 [0.81 to 1.08], AUCinf. 1.36 [1.24 ~1.49]). Therefore, no dose adjustment is required when this product is combined with CYP3A inhibitors.
Drugs that increase the pH of the stomach
Despite the pH-dependent in vitro water solubility of aletinib, a drug-drug interaction study specifically for 40 mg esomeprazole (a proton pump inhibitor) once daily demonstrated no clinically relevant effect of this combined dosing on the total exposure of aletinib and M4. Therefore, no dose adjustment is required for the combined administration of this product with proton pump inhibitors or other drugs that increase gastric pH (e.g., H2 receptor antagonists or antacids).
Effect of transporter proteins on the disposition of aletinib
In vitro data suggest that aletinib is not a substrate for P-gp. Alectinib and M4 are also not substrates of BCRP or organic anion transporting peptide (OATP) 1B1/B3. However, M4 is a substrate of P-gp. Alectinib has an inhibitory effect on P-gp, so it is not expected that the combined administration of alectinib and P-gp inhibitors will have a relevant effect on M4 exposure.
[Drug overdose].
No drug overdose occurred in clinical trials NP28761, NP28673 and BO28984. Patients who experienced an overdose should be closely monitored and provided with supportive treatment. There is no specific antidote for overdose of this product.
[Clinical Trials].
Patients not previously treated with crizotinib
The safety and efficacy of aletinib was evaluated in a global randomized, open, phase III clinical trial (BO28984) in patients with primary treatment of ALK-positive non-small cell lung cancer. Tissue samples from all patients were tested for positive ALK protein expression using Ventana anti-ALK (D5F3) immunohistochemistry (IHC) prior to randomization to the study.
A total of 303 patients were enrolled in the phase III trial, 151 of whom were randomized to the crizotinib arm and 152 to the alectinib arm, receiving oral treatment with this product at the recommended dose of 600 mg twice daily.
Stratification factors for randomization included Eastern Collaborative Oncology Group (ECOG) physical status score PS (0/1 vs. 2), ethnicity (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no). The primary endpoint of this clinical trial was progression-free survival (PFS) based on investigator-assessed (according to RECIST 1.1, the standard for evaluating efficacy in solid tumors), which proved superior to crizotinib. Baseline demographics and disease characteristics of the alectinib-treated group were: median age 58 years (54 years in the crizotinib group), 55% female (58% in the crizotinib group), 55% non-Asian (54% in the crizotinib group), 61% no history of smoking (65% in the crizotinib group), 93% with an ECOG PS score of 0 or 1 (93% in the crizotinib group), 97% developed stage IV disease (96% in the crizotinib group), 90% had adenocarcinoma histology (94% in the crizotinib group), 40% had CNS metastases at baseline (38% in the crizotinib group), and 17% had received prior CNS radiation therapy (14% in the crizotinib group).
The clinical trial met the primary endpoint at the time of the primary analysis. The effectiveness data are summarized in Table 5, and the Kaplan-Meier curve for investigator-assessed progression-free survival is shown in Figure 1. overall survival data were premature at the data cut-off date.
Table 5 Summary of efficacy results for study BO28984
Crizotinib
N=151 Arletinib
N=152 Median follow-up time (months)
17.6 (range: 0.3 – 27.0)18.6 (range: 0.5 – 29.0)Primary efficacy index PFS (INV)
Number of patients with events (%)
Median (months) [95% CI]
HR [95% CI]
p-value#
102 (68%)
11.1 [9.1; 13.1]
62 (41%)
NE [17.7; NE] 0.47 [0.34, 0.65]
p <0.0001 Secondary efficacy index PFS (IRC)*
Number of patients with events (%)
Median (months) [95% CI]
92 (61%)
10.4 [7.7; 14.6]
63 (41%)
25.7 [19.9; NE]HR [95% CI]
p-value #0.50 [0.36; 0.70]
p < 0.0001 to time to CNS progression (IRC)*, **
Number of patients with events (%) 68 (45%) 18 (12%) Cause-specific HR [95% CI]
p-value #0.16 [0.10; 0.28]
p < 0.0001 12-month cumulative incidence of CNS progression % [95% CI] 41.4% [33.2; 49.4] 9.4% [5.4; 14.7] ORR (INV)*
Number of patients in remission (%)
Number of CR patients (%)
114 (75.5%)
2 (1.3%)
126 (82.9%)
6 (3.9%) Median DOR (months) [95 % CI] 11.1 [7.9; 13.0] NE [NE; NE] CNS-ORR (IRC) in patients with measurable CNS metastases at baseline
Number of patients in CNS remission (%)
Number of patients with CNS-CR (%)
Median number of CNS-DOR (months) [95% CI]
N=22
11 (50.0%)
1 (5%)
5.5 [2.1, 17.3]
N=21
17 (81.0%)
8 (38%)
17.3 [14.8, NE] CNS-ORR in patients with measurable and non-measurable CNS metastases at baseline (IRC)
Number of patients in CNS remission (%)
Number of patients with CNS-CR
(%)
Median number of CNS-DOR (months) [95% CI]
N=58
15 (25.9%)
5 (9%)
3.7 [3.2, 6.8]
N=64
38 (59.4%)
29 (45%)
NE [17.3, NE]* key secondary endpoint of the rank test; #
Stratified rank test
** Competing risk analysis with CNS progression, systemic progression, and death as competing events
CI = confidence interval; CNS = central nervous system; CR = complete remission; DOR = duration of remission; HR = risk ratio; IRC = independent review committee; INV = investigator; NE = not estimable; ORR = objective remission rate; PFS = progression-free survival
For patients with CNS metastases at baseline (HR = 0.40, 95% CI: 0.25-0.64; median PFS not estimable in the alectinib group, 95% CI: 9.2-NE; median PFS in the crizotinib group = 7.4 months, 95% CI: 6.6-9.6) and for patients without CNS metastases at baseline (HR = 0.51, 95% CI. 0.33-0.80; median PFS not estimable in the alectinib group, 95% CI: NE-NE; median PFS = 14.8 months, 95% CI: 10.8-20.3 in the crizotinib group), the degree of benefit in progression-free survival was consistent, indicating that the benefit in the alectinib group was superior to that in the crizotinib group in both subgroups.
Figure 1 Kaplan Meier curve of investigator-assessed PFS in BO28984
Patients previously treated with crizotinib
Two phase I/II clinical trials (NP28673 and NP28761) were conducted to evaluate the safety and efficacy of alectinib in patients with ALK-positive non-small cell lung cancer who had previously received crizotinib.
Study NP28673
Study NP28673 is a Phase I/II single-arm, multicenter study conducted in patients with ALK-positive advanced non-small cell lung cancer who experienced disease progression while previously treated with crizotinib. Patients may have received prior chemotherapy in addition to crizotinib. A total of 138 patients were enrolled in the phase II portion of this study and received oral treatment with this product at the recommended dose of 600 mg twice daily.
The primary endpoint was the objective remission rate (ORR) in the total population (with and without prior cytotoxic chemotherapy) as assessed by the center’s independent review committee (IRC) (per RECIST 1.1). The co-primary endpoint is the objective remission rate (ORR) as assessed by the center IRC for patients previously exposed to cytotoxic chemotherapy treatment according to RECIST 1.1. The result was considered statistically significant if the lower confidence limit of the ORR estimate was above a pre-specified threshold (35%).
Patient demographics were consistent with the population of patients with ALK-positive non-small cell lung cancer. The baseline demographic and disease characteristics of the total study population were 67% Caucasian, 26% Asian, 56% female, and median age 52 years. Most patients had no history of smoking (70%), and 90.6% had a baseline ECOG (Eastern Collaborative Oncology Group) physical status score of 0 or 1, and 9.4% had 2. At study entry, 99% of patients had stage IV disease, 61% had brain metastases, and 96% had adenocarcinoma. Of the patients included in the study, 20% had prior disease progression after receiving crizotinib only and 80% had prior disease progression after receiving crizotinib and chemotherapy.
Study NP28761
Study NP28761 is a phase I/II single-arm, multicenter study in patients with ALK-positive advanced non-small press lung cancer whose disease progressed after prior treatment with crizotinib. Patients may have received prior chemotherapy in addition to crizotinib. A total of 87 patients were enrolled in the phase II portion of this study and received oral treatment with this product at the recommended dose of 600 mg twice daily.
The primary endpoint was the objective remission rate (ORR) as assessed by the central IRC according to RECIST version 1.1. The outcome was considered statistically significant if the lower confidence limit of the ORR estimate was above a pre-specified threshold (35%).
Patient demographics were consistent with the population of patients with ALK-positive non-small cell lung cancer. The demographic characteristics of the total study population were: 84% Caucasian, 8% Asian, 55% female, and a median age of 54 years. Most patients had no history of smoking (62%), and 89.7% had a baseline ECOG physical status score of 0 or 1 and 10.3% had a score of 2. At study entry, 99% of patients had stage IV disease, 60% had brain metastases, and 94% had adenocarcinoma. Of the patients included in the study, 26% had previously progressed disease after receiving crizotinib only and 74% had progressed disease after previous treatment with crizotinib and chemotherapy.
Table 6 summarizes the primary effectiveness results of study NP28673 versus NP28761, and a summary analysis of the CNS endpoints is summarized in Table 7.
Table 6 Effectiveness results of study NP28673 versus NP28761
NP28673
N=138NP28761
N=87Median follow-up time (months)21 (range: 1 – 30)17 (range: 1 – 29)Key effectiveness parameters ORR for RE population (IRC)
Number of patients in remission (%) [95% CI] N = 122 a
62 (50.8%) [41.6, 60.0]N = 67 b
35 (52.2%) [39.7, 64.6] ORR in patients with prior chemotherapy (IRC)
Number of patients in remission (%) [95% CI] N = 96
43 (44.8%) [34.6, 55.3]
Secondary effectiveness parameter DOR (IRC)
Number of patients with events (%)
Median (months) [95% CI] N = 62
36 (58.1%)
15.2 [11.2, 24.9] N = 35
20 (57.1%)
14.9 [6.9, NE] PFS (IRC)
Number of patients with events (%)
Median (months) [95% CI] N = 138
98 (71.0%)
8.9 [5.6, 12.8] N = 87
58 (66.7%)
8.2 [6.3, 12.6] CI =
confidence interval; DOR = duration of remission; IRC = independent review committee; NE = not estimable; ORR = objective remission rate; PFS = progression-free survival; RE =
Remission can be evaluated
a Based on the IRC determination, 16 patients did not have measurable lesions at baseline and therefore were not included in the remission evaluable population of the IRC.
b Based on the IRC determination, 20 patients did not have measurable lesions at baseline and were therefore not included in the remission evaluable population of the IRC.
ORR results for study NP28673 versus NP28761 were consistent across baseline patient characteristics (e.g., age, gender, ethnicity, ECOG physical status score, central nervous system (CNS) metastases, and prior chemotherapy) subgroups, especially when considering the small number of patients in some subgroups.
Table 7 Summary of the pooled analysis of CNS endpoints for study NP28673 versus NP28761
CNS metrics (NP28673 vs. NP28761) Patients with measurable CNS lesions at baseline with aletinib 600 mg twice daily
CNS ORR (IRC)
Number of patients in remission (%) [95% CI]
Complete remission
Partial remission
CNS DOR (IRC)
Number of patients with events (%)
Median (months) [95% CI]
N = 50
32 (64.0%) [49.2, 77.1]
11 (22.0%)
21 (42.0%)
N = 32
18 (56.3%)
11.1 [7.6, NE] CI = confidence interval; DOR = duration of remission; IRC = independent review committee; ORR = objective remission rate; NE = not estimable
Chinese data
Chinese patient subgroup data from global study BO28984
A total of 43 Chinese patients (18 in the crizotinib group and 25 in the alectinib group) were enrolled in the global clinical trial BO28984, of whom 10 were from mainland China, 19 from Hong Kong, China, and 14 from Taiwan, China. The efficacy data for the Chinese patient subgroup were consistent with the overall data in terms of the primary endpoint (investigator-assessed PFS) and key secondary endpoints (time to CNS progression as assessed by IRC, etc.). The median exposure time for aletinib in the Chinese patient subgroup was 13 months. Safety data for Chinese patients were consistent with the overall data.
Pharmacology and Toxicology]
Pharmacological effects
Alectinib is a highly selective and potent inhibitor of ALK and RET tyrosine kinases. In non-clinical studies, inhibition of ALK tyrosine kinase activity blocked the activation of downstream signaling pathways STAT3 and PI3K/AKT and induced tumor cell death (apoptosis).
Alectinib and the major metabolite (M4) inhibit mutant forms of ALK enzymes in vitro and in vivo, including mutant forms that lead to crizotinib resistance. The major metabolite of aletinib (M4) has similar potency and activity in vitro.
Non-clinical studies have shown that aletinib induces regression and prolonged survival in tumors carrying ALK fusion genes in non-clinical mouse xenograft tumor models, including animal models of intracranial tumors.
Toxicology Studies
General Toxicology
In repeated dosing toxicity tests in rats and monkeys, toxic target organs at clinically relevant exposure levels included, but were not limited to, the erythrocyte system, gastrointestinal tract, and hepatobiliary system.
Abnormal erythrocyte morphology was seen at exposures equal to or greater than 10%-60% (by AUC) of exposures at the recommended human dose administration. Extended mucosal proliferation zones in the gastrointestinal tract were seen in both rats and monkeys at exposures equal to or greater than 20%-120% of the AUC exposure at the recommended human dose. At exposures equal to or greater than 20%-30% of the recommended human dose (by AUC), not only elevated hepatic alkaline phosphatase (ALP) and direct bilirubin, but also vacuolation/degeneration/necrosis of the bile duct epithelium and enlarged/focal necrosis of hepatocytes were observed in rats and/or monkeys.
The results of general toxicology studies also showed no adverse effects on male and female reproductive organs in rats and monkeys at exposure levels equal to or greater than 2.6 and 0.5 times the recommended human dose (in terms of AUC).
Mild hypotensive effects were seen in monkeys at exposure levels near clinically relevant.
No separate juvenile animal studies were conducted. Dental and bone growth changes were observed in rats at doses equal to or greater than 4.5 times the recommended human dose, with dental changes including discoloration, changes in tooth size, and concomitant histopathological destruction of enamel-forming cells and dentin-forming cell layers. A reduction in bone trabeculae and increased osteoclast activity in the femur and sternum were also observed.
Genotoxicity
The results of the Ames test for alectinib were negative, while the results of the chromosomal aberration test for Chinese hamster lung (CHL) cells under metabolic activation conditions and the bone marrow micronucleus test for mice were positive.
Reproductive toxicity
Administration of aletinib during organogenesis in pregnant rats and rabbits at 2.7 times the recommended human dose (based on AUC) caused maternal toxicity and resulted in embryo-fetal toxicity and abortion. The same dose in pregnant rats resulted in small fetuses with delayed ossification and minor organ abnormalities. Pre-test results of embryo-fetal toxicity in rabbits showed that oral administration of aletinib at 27 mg/kg/day (about 2.9 times the AUC (0-24h,ss) of the human dose exposure) during organogenesis caused maternal toxicity and resulted in abortion and total embryo-fetal death in 3/6 pregnant rabbits and few surviving fetuses in the remaining 3 pregnant rabbits, visible reduction in fetal and placental weight, post-esophageal subclavian artery. Pre-test results of embryo-fetal toxicity in rats showed that oral administration of aletinib at 27 mg/kg/day (approximately 4.5 times the human dose exposure AUC (0-24h,ss)) during organogenesis caused total embryo-fetal loss in all pregnant rats; doses ≥9 mg/kg/day (approximately 2.7 times the human dose exposure AUC (0-24h,ss)) caused maternal toxicity and developmental toxicity, including reduced fetal weight, dilated renal pelvis, thymus cord, small ventricles and thin ventricular walls, and reduced number of sacral and caudal vertebrae.
Animal fertility studies have not been conducted to evaluate the effects of this product on fertility, and no effects on the reproductive organs of male or female animals have been observed in general toxicity studies.
Carcinogenicity
Carcinogenicity tests have not been conducted.
Other
Aletinib absorbs ultraviolet light at wavelengths of 200 to 400 nm, and an in vitro photosafety study in murine fibroblast cultures showed that aletinib may be phototoxic following UVA exposure.
Aletinib crossed the rat blood-brain barrier and remained in brain tissue, with CNS-plasma radioactivity ratios ranging from 0.9 to 1.5 at 24 hours post-dose.
Pharmacokinetics]
The pharmacokinetic parameters of aletinib and its major active metabolite (M4) were studied in patients with ALK-positive non-small cell lung cancer and in healthy subjects. The geometric means (coefficient of variation %) of steady-state Cmax, Cmin and AUC 0-12hr for aletinib were approximately 665 ng/mL (44.3%), 572 ng/mL (47.8%) and 7430 ng*h/mL (45.7%), respectively. geometric means (coefficient of variation %) of steady-state Cmax, Cmin and AUC 0-12hr for M4 were approximately 246 ng/mL (44.3%), 572 ng/mL (47.8%) and 7430 ng*h/mL (45.7%), respectively. ) were approximately 246 ng/mL (45.4%), 222 ng/mL (46.6%), and 2810 ng*h/mL (45.9%), respectively.
Absorption
After oral administration of 600 mg aletinib twice daily with meals in patients with ALK-positive non-small cell lung cancer, aletinib was rapidly absorbed, with blood levels peaking after approximately 4 to 6 hours.
Steady state was reached on day 7 after 600 mg twice daily and remained stable thereafter. For the 600 mg twice-daily dosing regimen, the geometric mean accumulation ratio estimated by population pharmacokinetic analysis was 5.6. Population pharmacokinetic analysis demonstrated a dose proportionality for aletinib at 300 to 900 mg after meals.
In healthy subjects, the absolute bioavailability of postprandial administration of aletinib was 36.9% (90% CI: 33.9%, 40.3%).
Following a single oral dose of 600 mg of aletinib with a high-fat, high-calorie meal, there was a 3-fold increase in exposure relative to fasting dosing (geometric mean ratio [90% CI] for combined exposure to aletinib and M4: Cmax: 3.31 [2.79 ~3.93], AUCinf: 3.11 [2.73 ~3.55]).
Distribution
Alectinib and its major metabolite M4 are highly bound to human plasma proteins (>99%), independent of drug concentration. At clinically relevant concentrations, the mean human blood-plasma concentration ratios of aletinib and M4 in vitro were 2.64 and 2.50, respectively.
The geometric mean of the steady-state volume of distribution (Vss) of aletinib after intravenous administration was 475 L, indicating that aletinib is widely distributed in tissues.
Metabolism
In vitro metabolism studies have shown that CYP3A4 is the major CYP isoenzyme mediating the metabolism of aletinib and its major metabolite, M4, accounting for an estimated 40-50% of aletinib metabolism in human hepatocytes. Results from human mass balance studies indicate that aletinib and M4 are the major circulating forms in plasma, with aletinib and M4 accounting for approximately 76% of the total radioactivity in plasma. The geometric mean ratio of metabolites/parent compound at steady state was 0.399.
Clearance
Following a single oral dose of 14C-labeled aletinib in healthy subjects, most of the radioactivity was excreted via the feces (mean recovery: 97.8%, range: 95.6%-100%), with minimal excretion in the urine (mean recovery: 0.46%, range: 0.30%-0.60%). Eighty-four percent and 5.8% of the dose was excreted in the feces as aletinib prodrug or M4, respectively.
The apparent clearance (CL/F) of aletinib was 81.9 L/h based on population pharmacokinetic analysis. The geometric mean of the individual elimination half-life of aletinib was estimated to be 32.5 h. The corresponding values for M4 were 217 L/h and 30.7 h, respectively.
Children
No pharmacokinetic studies have been conducted in the pediatric population.
Older adults
The results of a population pharmacokinetic analysis in patients aged 21-83 years indicate that age does not affect the exposure of this product.
Impaired Renal Function
Excretion of aletinib as prodrug from the urine and the active metabolite M4 is negligible (< 0.2% of the dose). Data obtained in patients with mild and moderate renal impairment suggest that renal impairment does not significantly affect the pharmacokinetics of aletinib. No formal pharmacokinetic studies have been conducted in patients with severe renal impairment, and no relevant population pharmacokinetic data have been collected. However, since renal excretion of aletinib is negligible, no dose adjustment is required in patients with impaired renal function.
Impaired hepatic function
Because the metabolism of aletinib is accomplished primarily through the liver, impaired hepatic function may increase the plasma concentration of aletinib and/or its major active metabolite, M4. Population pharmacokinetic analysis showed similar exposure to aletinib and M4 between patients with mildly impaired hepatic function (baseline total bilirubin ≤ ULN and baseline AST > ULN or baseline total bilirubin > 1.0-1.5 x ULN and any baseline AST) and normal hepatic function (total bilirubin ≤ ULN as well as AST ≤ ULN).
The combined exposure to aletinib and M4 was slightly increased in moderately (Child-Pugh Class B) hepatically impaired subjects following a single oral dose of 300 mg aletinib compared to healthy subjects (geometric mean ratio [90% confidence interval] for moderately hepatically impaired/healthy subjects: Cmax: 1.16 [0.786-1.72]. (AUCinf: 1.36 [0.947-1.96]). The combined exposure to aletinib and M4 increased more in subjects with severe (Child-Pugh Class C) hepatic impairment after a single oral dose of 300 mg aletinib compared to healthy subjects (geometric mean ratio [90% confidence interval] for those with severe hepatic impairment/healthy subjects: Cmax: 0.981 [0.517-1.86] AUCinf: 1.76 [0.984-3.15]).
Racial factors
The pharmacokinetic profile of aletinib and its main active metabolite (M4) was analyzed in 20 Chinese patients with non-small cell lung cancer.
The clinical pharmacokinetic profile of aletinib and M4 in Chinese patients after a single oral dose of aletinib 600 mg as well as multiple oral doses of aletinib 600 mg twice daily was generally consistent with that in white patients in the phase I/II clinical trial NP28763.
Storage]
Store in the original package under 30°C in a closed container, protected from light and moisture.
Special Use, Handling and Disposal Requirements
Do not use this product after the expiration date shown on the package.
Disposal of unused/expired drugs
The drug should be disposed of in the environment as little as possible. Do not dispose of medications through wastewater and avoid disposing of medications through household garbage. If your location provides services, use such recycling systems.
Packaging]
Double aluminum blister package
224 capsules/box (56 capsules/small box, 4 small boxes)
[Expiration date
36 months
Execution Standard
Import registration standard.
【Approval number】
【Manufacturer】
Company Name: Roche Registration GmbH
Address
Address: Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Production
Production
Factory: Excella GmbH & Co.
Location
Address: Nürnberger Strasse 12, 90537 Feucht, Germany
Package
Packaging
Plant: Delpharm Milano S.r.l.
Address: Via Carnevale 1, 20090 Segrate (MI), Italy
Domestic Contact: Shanghai Roche Pharmaceutical Co.
Location
Address: No. 1100 Longdong Avenue, China (Shanghai) Pilot Free Trade Zone
Tel
Tel: 021-28922888 (switchboard)
Fax
Fax: 021-50801800
Toll-free consultation: 8008208780 or 4008208780
As the instruction manual is updated quickly, for the latest approved Chinese instruction manual, please visit Roche China website: www.roche.com.cn.