Metastatic Breast Cancer

CANHERA"  is  indicated  for  the   treatment  of  MBC

patients who have human epidermal growth factor receptor 2- (HER2)-overexpressing tumours.

Early Breast Cancer (EBC)

CANHERA" is indicated for  the  treatment of  adult patients with HER2 positive EBC.

CANHERA"should only be used in MBC or EBC patients who have tumours with either overexpression of HER2 or HER2 gene amplification.

Metastatic Gastric Cancer (MGC)

CANHERA" in  combination with  capecitabine   or  5- fluorouracil and cisplatin is indicated for the treatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who  have not  received  prior  anti-cancer treatment for their metastatic disease.

CANHERA"should  be used in only those MGC patients whose tumours overexpress HER2,as defined by:

• IHC2+ plus  a confirmatory silver in situ hybridisation (SISH) or fluorescence in situ hybridisation (FISH) result,OR

•  IHC 3+ result

Before starting trastuzumab treatment. HER2 testing is mandatory.

• Administertrastuzumab as intravenous infusion.

• Trastuzumab is not to be administered as an intravenous push or bolus.

•  Do not mix with other drugs.

•  Patients with  MBC and MGC should be treated until disease progression.

•  Only a  physician experienced in the administration of  cytotoxic chemotherapy treatment should  initiate treatment. Only a healthcare professional should administer trastuzumab  and it should be administered by a healthcare  professional prepared  to  manage anaphylaxis and an emergency kit should be available  to  manage any   unexpected complications.

•  Loading  dose should  be administered  as a 90- minute intravenous infusion. If the initial loading dose is well tolerated, subsequent doses can be administered  as a 30-minute infusion.  Observe patients for at least six hours after the start of the first infusion and for two  hours after the start of subsequent infusions for symptoms like fever and chills or other infusion-related symptoms (see Undesirable Effects). If  a patient displays infusion-associated symptoms, the infusion may be interrupted to help control the symptoms;and may be resumed once the symptoms have abated.

Metastatic Breast Cancer

3-weeklydosing

• An   initial  loading dose of  8  mg/kg  is recommended;a maintenance dose of 6 mg/kg at

3-weekly  intervals is recommended, beginning  3 weeks after the loading dose.

• The loading  dose should be administered as an intravenous infusion over  approximately 90 minutes. The  subsequent doses  can  be administered as a 30-minute infusion, if the initial loading dose was well tolerated.

Weekly dosing

• An   initial  loading dose of  4  mg/kg  is recommended;a maintenance dose of 2 mg/kg at weekly intervals is recommended, beginning  one

week after the loading dose.

• The loading  dose should be administered as an intravenous infusion over approximately 90 minutes. The  subsequent doses can  be administered as a 30-minute infusion, if the initial loading dose was well tolerated.

Trastuzumab is indicated  as monotherapy in  patients who have already had two  or more chemotherapy regimens for metastatic disease. Prior chemotherapy must have been an anthracycline and a taxane (at least), unless patients  are unsuitable  for these treatments. Hormonal therapy must also have been tried, and have failed, in hormone receptor-positive patients (unless patients are unsuitable for hormonal therapy).

Trastuzumab is indicated in combination with  paclitaxel in patients  who  have not  received chemotherapy  for their metastatic disease and for whom an anthracycline is not suitable; in combination with  docetaxel in patients who have  not  received chemotherapy for  their metastatic disease; and  in combination with an aromatase inhibitor  in postmenopausal patients with hormone-receptor positive MBC, who  have not previously been treated with trastuzumab.

Administration in combination with paclitaxel or docetaxel

In clinical trials, paclitaxel or docetaxel was administered the  day following the  first  dose of trastuzumab (reference product).  If the dose was well tolerated, paclitaxeVdocetaxel was administered immediately after the subsequent doses of trastuzumab (reference product).

Administration in combination with an aromatase inhibitor

In a clinical trial, trastuzumab  (reference product)  and anastrozole were administered from day 1; without restrictions on the  relative timing  of  administration of trastuzumab (reference product) and anastrozole.

Early Breast  Cancer

Weekly dosing

Initialloading dose of 4 mglkg followed by 2 mg/kg every week concomitantly with  paclitaxel following chemotherapy with doxorubicin and cyclophosphamide. Three-weekly dosing

An initial  loading  dose of 8 mg/kg  is recommended;  a maintenance  dose of  6 mglkg at 3-weekly  intervals is recommended,  beginning   3  weeks  after  the  loading dose.

Trastuzumab is indicated  after  surgery, neoadjuvant  or adjuvant chemotherapy,and (if applicable) radiotherapy. Trastuzumab should  be   used after  adjuvant

chemotherapy with doxorubicin and cyclophosphamide,

in combination with paclitaxel or docetaxel.

Trastuzumab should  be used in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

Trastuzumab should  be used in combination with neoadjuvant chemotherapy followed by adjuvant trastuzumab therapy,  for locally advanced  disease (including inflammatory disease) or tumours of diameter

>2cm.

Metastatic Gastric Cancer

Three-weekly dosing

An initial  loading  dose of 8 mg/kg  is recommended;  a maintenance  dose of  6 mglkg at 3-weekly  intervals is recommended,  beginning  3  weeks  after  the  loading dose.

Duration of Treatment

Patients with  MBC or MGC should be treated with trastuzumab until disease progression. Patients with EBC should be treated with  trastuzumab  for  1 year or until disease recurrence, whichever  occurs first;  it is not recommended  to extend treatment in EBC beyond one year.

Dose Reduction

During periods of reversible chemotherapy-induced myelosuppression, trastuzumab  may be continued; but observe  the   patient  carefully for   complications of neutropenia. Chemotherapy  doses should be reduced or maintained as per the instructions for the specific regimen.

If  LVEF  drops  ;,1 0  ejection  fraction   (EF) points  from baseline and to  below  50%, treatment should  be stopped   and  a  repeat   LVEF assessment  should   be performed within  approximately 3  weeks. Discontinuation of trastuzumab should be strongly considered if LVEF does not improve, or declines further, or symptomatic  congestive heart failure (CHF) develops; unless the benefits outweigh the risks for the individual patient. All   such  patients  should   be  referred for assessment by a cardiologist and followed up.

Missed Doses

For a dose missed by s1  week, administer the usual maintenance  dose of trastuzumab  (weekly regimen:  2 mg/kg; three-weekly  regimen: 6 mg/kg), as soon as possible, without waiting till  the  next  planned  cycle. Subsequent maintenance  doses should  then  be given according to the previous schedule.

For a dose missed by >1 week, administer a re-loading dose of trastuzumab  (weekly regimen: 4 mg!kg; three­ weekly   regimen:  8  mg/kg)  over  approximately 90 minutes;  subsequent  maintenance  doses  (weekly regimen:   2  mg/kg; three-weekly regimen   5  mg/kg respectively) should  then  be  given  (weekly  regimen: every week; three-weekly regimen: every 3 weeks) from that point.

USE IN SPECIAL POPULATIONS'·'·"

From  available data, disposition of  trastuzumab (reference product)  is not altered  with  increasing age, renal impairment or serum creatinine levels. Elderly patients in reported clinical trials did not receive reduced doses.

Pregnancy  and   Lactation  (see   Warnings and

Precautions section)

Children

The safety and efficacy of  trastuzumab  has not  been established in  paediatric  patients  (below  18  years of age). Trastuzumab should not be used in these patients.

General

Initiate trastuzumab  therapy under the supervision of a physician experienced in cancer treatment.

Exacerbation of chemotherapy-induced neutropenia

Incidences of neutropenia,including febrile neutropenia, were reported in clinical  trials in patients  receiving trastuzumab  (reference product)  in  combination with myelosuppressive chemotherapy  as compared to those who  received chemotherapy   alone.  The incidence  of septic death was similar among patients who received trastuzumab (reference product) and those who did not. The risk of neutropenia  may be slightly increased when trastuzumab  is administered  with  docetaxel  following anthracycline therapy.

Infusion-related reactions

Serious   infusion-related  reactions to  trastuzumab (reference product)  infusion  have been reported;  and include dyspnoea, hypotension, wheezing, bronchospasm, tachycardia,reduced oxygen saturation, hypertension, supraventricular tachyarrhythmia, anaphylaxis, urticaria, angioedema and  respiratory distress. The majority  of  these events occur during  or within  2.5 hours of the start ofthe first infusion. Patients may be at increased risk of a fatal infusion reaction if they are  experiencing  dyspnoea at  rest,   arising from complications  of advanced malignancy or comorbidities. Should infusion reactions occur, discontinue trastuzumab infusion or slow the rate of infusion, and observe the patient  until  the symptoms resolve. Rarely, such reactions culminate in death.  Most  patients experienced resolution of symptoms and were given further infusions of trastuzumab (reference product). Supportive  therapy,   such  as  oxygen, epinephrine, antihistamine, bronchodilators, beta-agonists and corticosteroids, has been successfully used to treat serious reactions (see Undesirable Effects).

There have also been  reports  of  initial   improvement followed  by  delayed   reactions with  rapid   clinical deterioration. Within  hours   and  up  to  one  week following infusion,deaths  have occurred. Very rarely,the onset of infusion  symptoms and pulmonary  symptoms have occurred more than  6 hours after the start of the infusion.  Warn patients of the possibility of such a late onset and instruct them to contact the physician if these symptoms  occur. Prior to  resumption  of  trastuzumab (reference product)  infusion,  the  majority  of  patients who  experienced a severe infusion  reaction  were  pre­ medicated  with  antihistamines  and/or  corticosteroids. While  some patients  tolerated  trastuzumab  (reference product)  infusions, others had recurrent severe infusion

reactions despite pre-medications.

Pulmonary toxicity

Severe pulmonary  events  have  been  reported with trastuzumab  (reference product), occasionally resulting in death.Cases of interstitial  lung diseases including lung infiltrates,  acute  respiratory  distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress,  acute  pulmonary  oedema   and  respiratory insufficiency have been reported;these events may occur as part of an infusion-related reaction or with  a delayed onset.   Risk factors   associated  with   interstitial lung disease include prior or concomitant therapy with other anti-neoplastic  therapies such as taxanes, gemcitabine, vinorelbine  and  radiation  therapy.  Patients may be at greater risk of severe reactions if they have symptomatic intrinsic lung disease; or extensive tumour  involvement of  the  lungs, resulting  in dyspnoea at rest. Therefore, such patients  should not  be treated  with  trastuzumab (see   Contraindication). Exercise  caution for pneumonitis,  especially  in  patients being treated concomitantly with taxanes.

Cardiac dysfunction

Trastuzumab therapy increases the risk of CHF (New York Heart Association [NYHA] class II - IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving trastuzumab (reference product) alone or in combination with paclitaxel following anthracycline (doxorubicin or epirubicin). These events  can be moderate to severe and may be associated with  death. Caution should be taken when treating patients with increased cardiac risk (e.g., hypertension,  documented coronary artery disease, CHF, LVEF <55%,older age).

Since the half-life of trastuzumab is long,it may persist in the circulation for up to 27 weeks after stopping treatment. Patients who receive anthracyclines after stopping  trastuzumab  may possibly be at increased risk of  cardiotoxicity.  If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping treatment, and  monitor cardiac  function carefully if anthracyclines are used. If left ventricular function continues  to  decrease, but  patients  remain asymptomatic, the  physician should consider discontinuing therapy if no clinical benefit of therapy has been seen. Trastuzumab and anthracycline should not be given  concurrently   in  the  adjuvant  treatment  setting (EBC) or MBC setting. In patients  with  EBC eligible for neoadjuvant-adjuvant  chemotherapy, trastuzumab should only be used concurrently  with  anthracyclines in chemotherapy-naive patients and only with  low-dose anthracycline  regimens (maximum  cumulative  doses of doxorubicin   180  mg/m' or  epirubicin  360  mg!m').   In patients  being  concurrently  treated  with full course of low-dose anthracyclines and trastuzumab in the neoadjuvant setting, additional cytotoxic chemotherapy should not be given after surgery.

Patients who  are going to start trastuzumab, especially those with  prior  exposure to  anthracycline and cyclophosphamide, should   undergo   baseline  cardiac assessment, including history and physical examination, ECG, echocardiogram  and/or   multigated  acquisition (MUGA)   scan.  Repeat  cardiac  assessments every  3 months during treatment and every 6 months following discontinuation of treatment until  24 months  from the last administration oftrastuzumab.

If LVEF drops 0!!1 0 EF points from baseline and to below 50%,  treatment should be stopped  and a repeat LVEF assessment should be performed  within approximately 3 weeks. If LVEF does not improve, or declines further, or symptomatic  CHF  develops, discontinuation  of trastuzumab  should be strongly considered, unless the benefits for the individual patient outweigh the risks. All such patients  should  be  referred  for  assessment by a cardiologist and followed up.

No prospective study has been done  on the safety of continuing or resuming trastuzumab (reference product) in patients who  experience cardiotoxicity. In the pivotal trials,  most patients who  developed heart  failure improved with  standard treatments (including  diuretics, cardiac glycosides, beta blockers and/or angiotensin converting enzyme inhibitors). In these trials, most patients with  cardiac symptoms who also had evidence of a clinical benefit from trastuzumab (reference product) treatment continued on therapy  with trastuzumab (reference  product) without further clinical  cardiac events.

In a global early breast cancer trial with trastuzumab (reference product),  patients with  the   following conditions were excluded:

• History of myocardial infarction

• Angina pectoris requiring medical treatment

• Clinically significant cardiac valvular disease

• History of existing cardiac heart failure (NYHA II

-IV)

• Other  cardiomyopathy, cardiac arrhythmia requiring medical treatment

• Poorly controlled hypertension

• LVEF<55%

• hemodynamic effective pericardia! effusion Therefore, the benefit-risk  balance for such patients  is unknown,and treatment is not recommended.

Benzyl alcohol

Benzyl  alcohol  (1.1 %)  is  used  as  a  preservative  in bacteriostatic water for injection in the 1 50 mg and 440 mg CANHERA"multi-dose vials. If a patient is known to be hypersensitive to benzyl alcohol, reconstitute CANHERA" with  water  for  injection,  and use only one dose per CANHERA" vial. Discard any unused portion.

Fertility,pregnancy and lactation

Women of childbearing potential

Women  of childbearing  potential should be advised to use effective contraception during treatment with trastuzumab  and for 7 months  after treatment has concluded.

Formal drug  interaction studies with trastuzumab (reference product) have not been performed in humans. In clinical trials of trastuzumab (reference product), no clinically significant interactions with the concomitant medications  used were observed (see Pharmacokinetic Properties). The results of a small sub-study suggested that  the  exposure  to  the  bioactive  metabolites  (e.g.,5-fluorouracil) of capecitabine  was not affected  by concurrent   use of  cisplatin  or  by  concurrent   use of cisplatin plus trastuzumab (reference product). However, capecitabine itself showed higher concentrations  and a longer   half-life  when   combined with  trastuzumab (reference product).  The   mean serum trough concentration of trastuzumab  (reference product)  was consistently  elevated   approximately 1.5-fold,  when administered in combination with paclitaxel as compared to trough  concentrations of trastuzumab (reference product)  when administered in combination with  an anthracycline  and cyclophosphamide. Trastuzumab can increase the  overall  exposure of  7-deoxy-13  dihydro­ doxorubicinone (D7D), a doxorubicin  metabolite.  The bioactivity of D7D and the clinical impact of the increase of this metabolite is not clear.

Pregnancy

Reproduction studies have  been  performed in cynomolgus monkey at doses up to 25 times the weekly human dose and have revealed no evidence of impaired fertility or harm to the fetus due to trastuzumab. Placental transfer of trastuzumab during the early (days 20-50 of gestation) and late (days 120-150 of gestation) foetal development period was observed. It is not known whether  trastuzumab  can affect  reproductive  capacity. As animal reproduction studies are not always predictive of  human  response, trastuzumab   should  be  avoided during  pregnancy  unless the  potential  benefit  for  the mother outweighs the potential risk to the foetus.

In  the  post-marketing  setting,  cases of  foetal  renal growth  and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus,have been reported in pregnant women receiving trastuzumab. Women who become pregnant should be advised of the possibility of harm to the   foetus.  If  a  pregnant  woman  is  treated with trastuzumab, or  if  a patient  becomes pregnant  while receiving trastuzumab  or within 7 months following the last dose of trastuzumab, close monitoring by a multidisciplinary team is desirable.

Breast-feeding

A study conducted  in lactating Cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose demonstrated  that  trastuzumab  is secreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated with  any adverse effects on their growth or development  from birth  to 1 month  of age. It is not known  whether  trastuzumab  is secreted in human milk. As human lgG1 is secreted into human milk, and the  potential  for  harm  to  the infant  is unknown, women  should not  breast-feed during  CANHERA"150 mg therapy and for 7 months after the last dose.

Fertility

There is no fertility data available.

Effects on Ability to Drive and Use Machines Trastuzumab has no or negligible influence on the ability to drive or use machines. Patients should be advised not to  drive  and  use  machines  if  they  are  experiencing infusion-related symptoms;until the symptoms abate. 

The following undesirable effects are based on publicly available  information categorized on  the  basis of frequency of occurrence of adverse reactions in different clinical  trials   and   post-marketing information for trastuzumab (reference product).

Very   common ('!!.111 0):   Tremor, blood  pressure decreased,blood pressure increased, heart beat irregular, palpitation, cardiac flutter,  lip  swelling,  swelling  face, muscle tightness (adverse reactions reported  largely in association  with   infusion-related reactions);  ejection fraction  decreased (observed with  combination therapy following anthracyclines and combined  with  taxanes); wheezing (adverse reactions reported in association with a  fatal  outcome and   infusion-related reactions); dyspnoea (adverse reactions reported in association with a  fatal  outcome);  infection,  nasopharyngitis, febrile neutropenia, anaemia, neutropenia, leukopenia, thrombocytopenia, weight decreased/weight loss,anorexia, weight increased, decreased appetite,
insomnia, dizziness, headache, paraesthesia, hypoaesthesia, dysgeusia, conjunctivitis, lacrimation increased, lymphoedema, hot flush, cough, epistaxis,
rhinorrhoea, oropharyngeal pain, diarrhoea, vomiting, nausea, abdominal pain, dyspepsia, constipation, stomatitis, erythema, rash, alopecia, nail disorder, Palmar-plantar erythrodysaesthesia syndrome, arthralgia, myalgia, asthenia, chest pain, chills, fatigue, influenza-like symptoms, infusion-related reaction, pain, pyrexia, mucosal inflammation, peripheral oedema, nail toxicity.

Common (?.1 /100 to <1 /10):

Cardiac failure(congestive), pneumonia, pleural effusion (adverse reactions reported in association with a fatal outcome); supraventricular tachyarrhythmia, hypotension (adverse reactions reported in association with a fatal outcome and infusion-related reactions); neutropenic sepsis, cystitis,
herpes zoster, influenza, sinusitis, skin infection, rhinitis, upper respiratory tract infection, urinary tract infection, erysipelas, cellulitis, pharyngitis, hypersensitivity, anxiety, depression, thinking abnormal, peripheral neuropathy, hypertonia, somnolence, ataxia, dry eye, cardiomyopathy, hypertension, vasodilatation, asthma, lung disorder, pancreatitis, haemorrhoids, dry mouth, hepatocellular injury, hepatitis, liver tenderness, acne, dry skin, ecchymosis, hyperhydrosis, maculopapular rash, pruritus, onychoclasis, dermatitis, arthritis, back pain, bone pain, muscle spasms, neck pain, pain in extremity, renal disorder, breast inflammation/mastitis, malaise, oedema, contusion_

Uncommon (?.111,000 to <11100): Sepsis, deafness,
pericardia I effusion, urticaria_

Rare (?.1110,000 to <111,000): Paresis, pneumonitis,
jaundice.

Not known (cannot be estimated from the available
data): Anaphylactic reaction, anaphylactic shock, pulmonary fibrosis, respiratory distress, respiratory failure, lung infiltration, acute pulmonary oedema, acute respiratory distress syndrome, bronchospasm, hypoxia, oxygen saturation decreased (adverse reactions reported in association with a fatal outcome); malignant neoplasm progression, neoplasm progression, hypoprothrombinaemia, hyperkalaemia, brain oedema, papilledema, retinal haemorrhage, cardiogenic shock, pericarditis, bradycardia, gallop rhythm present, laryngeal oedema, pharyngolaryngeal pain, pulmonary hypertension, Herpes simplex, hypokalaemia, dysphagia, accidental injury, thrombosis/embolism, sudden death, autoimmune thyroiditis, flu syndrome, allergic reaction, orthopnoea, pulmonary oedema, interstitial lung disease, hepatic failure, angioedema, dermatitis, urticaria, glomerulonephritis membranous, glomerulonephropathy, renal failure, oligohydramnios, renal hypoplasia, pulmonary hypoplasia. The most serious and/or common adverse reactions reported with trastuzumab (reference product) are: cardiac dysfunction, infusion-related reactions and hypersensitivity, haematological toxicity, infections and pulmonarytoxicity.

Cardiac dysfunction
CHF (NYHA II-IV) is a common adverse reaction observed with trastuzumab (reference product) and has been associated with fatal outcome. Signs and symptoms of cardiac dysfunction observed in patients treated with trastuzumab (reference product) include: dyspnoea, orthopnoea, increased cough, pulmonary oedema, 53 gallop or reduced ventricular ejection fraction (see Warnings and Precautions).

Infusion-related reactions (IRRs) and Hypersensitivity
The following infusion-related reactions (IRRs) were seen in all trastuzumab (reference product) trials: chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress (see Warning and Precautions). Majority of IRRs are mild to moderate in intensity; usually occur during first, second or third infusion and lessen in frequency in subsequent infusions. Anaphylactoid reactions have been observed with trastuzumab (reference product) in isolated cases.

Haematological toxicity
Febrile neutropenia is the most common haematological toxicity observed with trastuzumab (reference product). The common haematological toxicity are: anaemia, leukopenia, thrombocytopenia and neutropenia. When trastuzumab is administered with docetaxel following anthracycline therapy, the risk of neutropenia may be slightly increased.

Infections

In the adjuvant setting, the most common sites of infections include upper respiratory tract, skin and urinary tract.

Pulmonary toxicity
The following pulmonary adverse reactions were observed with trastuzumab (reference product): pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency.

There is no information on overdose from human clinical trials. Single doses greater than 10 mg/kg oftrastuzumab (reference product) alone have not been administered in the clinical trials. Doses up to this level were well tolerated.

Pharmacodynamic Properties
Pharmacotherapeutic group: Antineoplastic agents,
monoclonal antibodies
ATC code: L01 XC03'
Mechanism of Action'·'·'
Trastuzumab is a humanised monoclonallgG 1 antibody produced by recombinant DNA technology; and contains complementarity-determining regions from a mouse antibody (anti-p185) specific for the extracellular domain ofthe human epidermal growth factor receptor 2 protein (HER2), along with human framework sequences.
The HER2 receptor becomes constitutive instead of inducible in tumour cells. This is a result of increased cell surface expression/overexpression of HER2 protein caused by HER2 gene amplification. Overexpression is seen in 25% to 30% of primary breast cancers and in 6.8% to42.6% gastric cancers.

Studies showed that amplification or overexpression of HER2 correlates with shorter disease-free survival.

Trastuzumab binds to sub-domain IV, a juxta membrane region of HER2's extracellular domain, with high affinity and specificity. This binding inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of HER2.

In in-vitro assays and in animals, trastuzumab is reported to have inhibited proliferation of human tumour cells overexpressing HER2. Trastuzumab also preferentially mediates antibody-dependent cell-mediated cytotoxicity (ADCC) on tumour cells overexpressing HER2.

Pharmacokinetic Properties
Two phase 1 studies

1) Single-center, single-dose, 2- period, randomized, double-blind, cross-over study and
2) Single-center, randomized, double-blind, three-arm, parallel-group study were conducted in normal healthy volunteers. Both studies showed that pharmacokinetic profile of CANHERA"was similar to that of trastuzumab (reference product). In addition, a multicenter, doubleblind, randomized, parallel-group, phase Ill study showed that pharmacokinetic, efficacy, safety and immunogenicity profiles of CANHERA" was similar to trastuzumab (reference product) in patients with HER2- positive metastatic breast cancer (MBC).
Pharmacokinetics in Special Populations'A"
The pharmacokinetics of trastuzumab (reference product) have not been studied specifically in elderly patients, patients with renal impairment, or patients with hepatic impairment. However, in the trials conducted with trastuzumab (reference product), distribution and elimination were not noted to be affected by age and renal impairment (see Dose and Method of Administration).

Nonclinical studies (conventional toxicity  studies) on CANHERA" did not  indicate  any special hazard for humans. During conventional single- and repeat-dose toxicity  studies of  CANHERA" in mice and rabbits,  no clinically relevant adverse events were observed at the highest  dose  levels tested.  Local tolerance  was  also evaluated  in  these  toxicity  studies, and  no  clinically

relevant effects  were  observed. Two comparative nonclinical studies undertaken  in cynomolgus  monkeys showed   that  the  pharmacokinetic  and  toxicokinetic profile of CANHERA"was similar to that of trastuzumab (reference product).

THERAPEUTIC INDICATIONS Metastatic Breast Cancer

CANHERA"  is  indicated  for  the   treatment  of  MBC

patients who have human epidermal growth factor receptor 2- (HER2)-overexpressing tumours.

Early Breast Cancer (EBC)

CANHERA" is indicated for  the  treatment of  adult patients with HER2 positive EBC.

CANHERA"should only be used in MBC or EBC patients who have tumours with either overexpression of HER2 or HER2 gene amplification.

Metastatic Gastric Cancer (MGC)

CANHERA" in  combination with  capecitabine   or  5- fluorouracil and cisplatin is indicated for the treatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who  have not  received  prior  anti-cancer treatment for their metastatic disease.

CANHERA"should  be used in only those MGC patients whose tumours overexpress HER2,as defined by:

• IHC2+ plus  a confirmatory silver in situ hybridisation (SISH) or fluorescence in situ hybridisation (FISH) result,OR

•  IHC 3+ result.

List of Excipients:
L-Histidine,

L-Histidine hydrochloride,

Polyethylene Glycol3350 (Macrogol3350),

D-Sorbitol.

CANHERA" should not be mixed or diluted with other products except those mentioned under Special Precautions for Disposal and Other Handling section. Do not dilute with glucose solutions, since these cause aggregation ofthe protein.

STORAGE AND HANDLING INFORMATION
Store vials at 2"C to S"C prior to reconstitution.
Store away from light.
Vials should not be used beyond the expiration date
stamped on the vial; the reconstituted drug solution
should be used as given below; and any unused portion
must be discarded. DO NOT FREEZE DRUG THAT HAS
BEEN RECONSTITUTED.

PACKAGING INFORMATION
150 mg CAN HERA" (Single-dose vial)
CANHERA" finished product 150 mg is filled in 15 ml USP type 1 glass vial, closed with a halobutyl rubber stopper and sealed with 20MM lavender flip-off seal.
150 mg CANHERA"(Multi-dosevial)
CANHERA" finished product 150 mg is filled in 15 mL USP type 1 glass vial, closed with a halobutyl rubber stopper and sealed with 20MM lavender flip-off seal.
The 150 mg pack is provided with total 1 0 ml bacteriostatic water for injection (containing 1.1% benzyl alcohol as preservative), of which 7.2 ml is to be used for reconstitution.
440 mg CANHERA"(Multi-dosevial)
CANHERA" finished product 440 mg is filled in 50 mL USP type 1 glass vial closed with a halobutyl rubber stopper and sealed with 20MM lavender flip-off seal.
The 440 mg pack is provided with total 20 ml bacteriostatic water for injection (containing 1.1% benzyl alcohol as preservative) for reconstitution.

Shelf-life of the reconstituted solution
1 SO mg (Single-dose use vial)
The reconstituted product is physically and chemically
stable for 4S hours at 2°C to soc after dissolving in sterile
water for injection (not supplied). From a microbiological
safety perspective, the reconstituted solution should be
used immediately. Do not freeze the reconstituted
solution.
440 mg/150 mg (Multi-dose use vials)
Reconstituted solutions made with bacteriostatic water
for injection, as supplied, are stable (physico-chemically
and microbiologically) for 2S days, when refrigerated at
2°( to soc. The reconstituted solution is suitable for
multiple uses, as it contains preservative. Discard any
remaining reconstituted solution after 2S days. Do not
freeze the reconstituted solution.
Shelf-life of the solution for infusion containing
the reconstituted product
150 mg (single-dose and multi-dose use vials) and
440 mg (multi-dose use vials)
Infusion solution (0.9% sodium chloride) containing the
reconstituted drug product is physically and chemically
CHECKED BY:
DATE:
stable for 24 hours at 2°C to soc. From the perspective
of microbiological safety, the CANHERA" infusion
solution should be used immediately, unless
reconstitution and dilution have taken place under
aseptic conditions. If reconstitution and dilution have
taken place under aseptic conditions, the infusion
solution can be stored up to 24 hours when refrigerated
at 2°C to soc.
Special Precautions for Disposal and Other
Handling
• Appropriate aseptic technique should be used.
• Use of other reconstitution solvents should be
avoided.
Reconstitution details are given in the table below:
Table 2: Reconstitution Details of 150 mg
(Single- and Multi-dose Use)
and 440 mg Vials (Multi-dose Use)
Type of Vial Reconstitution
150 mg 7.2 ml of sterile
(single-dose) water for injection*
150 mg 7.2 ml of BWFI
(multi-dose) (containing 1.1%
benzyl alcohol)
440mg 20 ml of BWFI
(multi-dose) (containing 1.1%
benzyl alcohol)
BWFI: bacteriostatic water for injection.
*Not supplied
Trastuzumab pH
mg/ml
-21 -6.0
-21 -6.0
-21 -6.0
• During reconstitution, handle CANHERA"
carefully. Causing excessive foaming during
reconstitution or shaking the reconstituted
solution may result in problems with the amount
of CAN HERA" that can be withdrawn from the
vial.
• Do not freeze the reconstituted solution.
Instructions for reconstitution-150 mg vial
(single -dose via/1
1) Slowly inject 7.2 ml of sterile water for injection into
the vial containing the lyophilized CAN HERA", using a
sterile syringe. Direct the stream into the lyophilized
cake.
2) To aid reconstitution, the vial should be swirled gently.
DO NOT SHAKE.
Instructions for reconstitution-150 mg vial
(multi-dose vial)
1) Slowly inject 7.2 ml of bacteriostatic water for
injection into the vial containing the lyophilized
CANHERA", using a sterile syringe. Direct the stream into
the lyophilized cake.
2) To aid reconstitution, the vial should be swirled gently.
DO NOT SHAKE.
Instructions for reconstitution-440 mg vial
(multi-dose vial)
1) Slowly inject 20 ml of bacteriostatic water for
injection into the vial containing the lyophilized
CANHERA", using a sterile syringe. Direct the stream into
the lyophilized cake.
2) To aid reconstitution, the vial should be swirled gently.
DO NOT SHAKE.
Slight foaming of the product may be seen upon
reconstitution; this is not unusual. The vial should be
allowed to stand undisturbed for approximately 5
minutes. Reconstituted CANHERA"is a colourless to pale
yellow, transparent solution. No particles should be
visible.
Instructions for dilution:
Determine the volume of CAN HERA "solution required:
• Based on a loading dose of 4 mg CANHERA"Ikg, or
D:\e drive\Jobs G Drive Data\HEALTH CAREIPACKAGING\INTERNATIONAL\CANHERA (SAUDI) SFDA\CANHERA PI FOR MOH SUBMISSION
asubsequentweeklydoseof2 mg CANHERA"/kg:
Body weight (kg) x dose
(4 mglkg for loading or 2 mglkg for maintenance)
Volume (mL) = __:____:,~----=-----=---=-----__:__
21 (mg/mL, concentration of reconstituted solution)
• Based on a loading dose of S mg CANHERA"fkg, or
a subsequent 3-weekly dose of 6 mg CANHERA"
/kg:
Body weight (kg) x dose
(8 mglkg for loading or 6 mg/kg for maintenance)
Volume (mL) = __::___::_:_ _ _:_ ___:__:, ___ __:__
21 (mglmL, concentration of reconstituted solution)
• Withdraw the appropriate amount of solution from
the vial, and add it to an infusion bag containing
250 mL of 0.9% sodium chloride solution.
• Glucose/dextrose-containing solutions should not
be used.
• Mix the solution by inverting the bag gently (to
avoid foaming).
• Once the infusion is prepared it should be
administered immediately.
• If diluted aseptically, it may be stored for 24 hours
(do not store above 30°().
Inspect visually for particulate matter and discoloration
prior to administration.
No incompatibilities have been observed between
trastuzumab and polyvinylchloride, polyethylene or
polypropylene bags.
Dispose of unused medicinal product in accordance with
local regulations.