Alpelisib

Registered South African indications:

• Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated advanced or metastatic breast cancer
  - In postmenopausal women, and men in combination with fulvestrant following progression on or after an endocrine-based regimen

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

South African manufacturer recommendations

• Females of reproductive potential and for 1 week after the last dose
• Male patients with sexual partners of reproductive potential and for 1 week after the last dose
• Fertility in males and females of reproductive potential
• Severe renal impairment (CrCl<30ml/min)
• History of severe cutaneous reactions
• Diabetes mellitus or history thereof
• Poor glycaemic control
• Coadministration of or prior exposure to bisphosphonates
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Females of reproductive potential and for 1 week after the last dose
• Male patients with sexual partners of reproductive potential and for 1 week after the last dose
• Breastfeeding
• Fertility in males and females of reproductive potential
• Severe renal impairment (CrCl<30ml/min)
• Elderly (≥75 years)
• Prior fulvestrant use
• History of severe cutaneous reactions
• Type 2 diabetes mellitus or history thereof
• Type 1 and uncontrolled type 2 diabetes mellitus
• Symptomatic visceral disease
• Ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates/denosumab
• Coadministration or sequential use of bisphosphonates or RANK-ligand inhibitors
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Treatment with alpelisib should be initiated by a medical practitioner experienced in the use of anticancer therapies

Used for the treatment of

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated advanced or metastatic breast cancer (Additional agent required)
- In postmenopausal women, and men in combination with fulvestrant following progression on or after an endocrine-based regimen

• Oral (fct): 300mg, once daily continuously

---

Patients with HR-positive, HER2-negative advanced breast cancer should be selected for treatment with alpelisib based on the presence of a PIK3CA mutation in tumour or plasma specimens, using a validated test. If a mutation is not detected in a plasma specimen, tumour tissue should be tested if available

---

Alpelisib should be taken immediately after food, at approximately the same time each day on a continuous basis. Swallow alpelisib tablets whole. Tablets should not be chewed, crushed or split prior to swallowing. No tablet should be ingested if it is broken, cracked, or otherwise not intact

---

If a dose is missed, it can be taken immediately following food and within 9 hours after the time it is usually taken. After more than 9 hours, the dose should be skipped for that day. On the next day, alpelisib should be taken at the usual time. If the patient vomits after taking the dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time

---

When given with alpelisib, the recommended dose of fulvestrant is 500mg administered on Days 1, 15, and 29, and once monthly thereafter. Please refer to the full prescribing information for fulvestrant

---

See additional prescribing points for the recommended dose modifications for adverse reactions

---

International manufacturer recommendations

Treatment with alpelisib should be initiated by a physician experienced in the use of anticancer therapies

Used for the treatment of

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer (Additional agent required)
- In combination with fulvestrant for the treatment of postmenopausal women, and men with a PIK3CA mutation after disease progression following endocrine-based therapy

• Oral (fct): 300mg, once daily; Max: 300mg/24hrs

---

Patients with HR-positive, HER2-negative advanced breast cancer should be selected for treatment with alpelisib based on the presence of a PIK3CA mutation in tumour or plasma specimens, using a validated test. If a mutation is not detected in a plasma specimen, tumour tissue should be tested if available

---

Alpelisib should be taken immediately after food, at approximately the same time each day. The tablets should be swallowed whole. They should not be chewed, crushed or split prior to swallowing. Tablets that are broken, cracked or otherwise not intact should not be ingested

---

If a dose of alpelisib is missed, it can be taken immediately following food and within 9 hours after the time it is usually administered. After more than 9 hours, the dose should be skipped for that day. On the next day, alpelisib should be taken at the usual time. If the patient vomits after taking the dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time

---

Alpelisib should be coadministered with fulvestrant. The recommended dose of fulvestrant is 500mg administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the full prescribing information of fulvestrant

---

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose modifications may be necessary to improve tolerability (See additional prescribing points)

Not established for use in children below 18 years

Pregnancy

South African manufacturer recommendations

• Contraindicated
• Alpelisib should not be used during pregnancy
• Based on animal data and its mechanism of action, alpelisib can cause foetal harm when administered to a pregnant woman
• Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryo-toxicity, foeto-toxicity, and teratogenicity
• Females of reproductive potential should be advised that animal studies and the mechanism of action have shown that alpelisib can be harmful to the developing foetus
• Females of reproductive potential should use effective contraception during treatment with alpelisib and for 1 week after the last dose
• It is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives
• Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms and effective contraception during alpelisib treatment and for 1 week after the last dose

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• Alpelisib is indicated in men and postmenopausal women. It is not to be used in women who are, or may be, pregnant or breastfeeding
• Alpelisib is not indicated and is not to be used in women who are, or may be, pregnant
• There are no data from the use of alpelisib in pregnant women
• Studies in animals have shown reproductive toxicity
• Alpelisib is not recommended during pregnancy and in women of childbearing potential not using contraception
• The pregnancy status of females of reproductive potential should be verified prior to starting treatment with alpelisib
• Females of reproductive potential should be advised that animal studies and the mechanism of action have shown that alpelisib can be harmful to the developing foetus
• Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity
• In case females of reproductive potential take alpelisib they should use effective contraception (e.g. double-barrier method) when taking alpelisib and for at least 1 week after stopping treatment with alpelisib
• Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms during sexual intercourse while taking alpelisib and for at least 1 week after stopping treatment with alpelisib

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• It is not known if alpelisib is excreted in human or animal milk
• Because of the potential for serious adverse reactions in the breastfed infant, it is recommended that women should not breastfeed during treatment and for at least 1 week after the last dose of alpelisib

International manufacturer recommendations

• Caution; not recommended 
• Alpelisib is indicated in men and postmenopausal women. It is not to be used in women who are, or may be, pregnant or breastfeeding
• It is not known if alpelisib is excreted in human or animal milk
• Because of the potential for serious adverse reactions in the breastfed infant, it is recommended that women should not breastfeed during treatment and for at least 1 week after the last dose of alpelisib

Fertility

• There are no data on the effects of alpelisib on fertility
• Based on repeated dose toxicity studies in animals, alpelisib may impair fertility in males and females of reproductive potential

Renal Impairment

• Mild to moderate (CrCl 30-<90ml/min): No dose adjustment recommended 
• Severe (CrCl<30 ml/min): Caution; no information available 

Hepatic Impairment

• No dose adjustment recommended 

Elderly

South African manufacturer recommendations

• No dose adjustment recommended 

International manufacturer recommendations

• Caution; no dose adjustment recommended 
  There are limited data in patients aged ≥75 years, and especially for those ≥85 years

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dysgeusia
  - Ageusia
  - Hypogeusia
• Fatigue
• Insomnia

Cardiovascular Disorders

• Hypertension

Respiratory Disorders

• Pneumonitis
• Interstitial lung disease

Gastrointestinal Disorders

• Diarrhoea
  (See additional prescribing points)
• Nausea and vomiting
• Stomatitis
• Aphthous ulcer
• Mouth ulceration
• Abdominal pain
• Dyspepsia
• Toothache
• Gingivitis
• Gingival pain
• Cheilitis
• Pancreatitis
• Increased lipase
• Dry mouth

Hepatobiliary Disorders

• Increased gamma-glutamyltransferase
• Increased alanine aminotransferase
• Prolonged activated partial thromboplastin time
• Decreased albumin

Genitourinary Disorders

• Urinary tract infection
• Increased blood creatinine
• Acute kidney injury
• Urosepsis
• Vulvovaginal dryness

Endocrine and Metabolic Disorders

• Hyperglycaemia
  (See additional prescribing points)
• Increased plasma glucose
• Decreased plasma glucose
• Decreased appetite
• Hypokalaemia
• Hypocalcaemia
• Decreased magnesium
• Decreased weight
• Dehydration
• Ketoacidosis
• Diabetic ketoacidosis
• Hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS)

Musculoskeletal Disorders

• Muscle spasms
• Myalgia
• Osteonecrosis of jaw
  (See additional prescribing points)

Skin and Subcutaneous Tissue Disorders

• Rash
  - Maculopapular rash
  - Macular rash
  - Generalised rash
  - Papular rash
  - Pruritic rash
• Alopecia
• Pruritus
• Dry skin
• Skin fissures
• Xerosis
• Xeroderma
• Mucosal inflammation
• Mucosal dryness
• Erythema
  - Generalised erythema
• Dermatitis
  - Acneiform dermatitis
• Palmar-plantar erythrodysaesthesia syndrome
• Erythema multiforme
• Stevens-Johnson syndrome
• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Decreased lymphocyte count
• Decreased platelet count
• Hypersensitivity
  (See additional prescribing points)
  - Allergic dermatitis
• Increased glycosylated haemoglobin
• Oedema
  - Peripheral oedema
  - Face swelling
  - Face oedema
• Lymphoedema
• Pyrexia

Sensory Disorders

• Blurred vision
• Dry eye
• Eyelid oedema

• Sensitive breast cancer resistant protein (BCRP) substrates
• Strong CYP3A4 inducers
• BCRP inhibitors
• Eltrombopag
• Lapatinib
• Pantoprazole
• CYP3A4 substrates possessing an additional time-dependent inhibition and induction potential
• Rifampicin
• Ribociclib
• Encorafenib
• CYP2C9 substrates with narrow therapeutic index
• Warfarin
• CYP2B6 sensitive substrates with narrow therapeutic index
• Bupropion
• Sensitive OAT3 drug transporter substrates
• Sensitive P-glycoprotein (P-gp) substrates
• Bisphosphonates
• Receptor activator of nuclear factor kappa-B (RANK)-ligand inhibitors
• Denosumab

• PIK3CA mutation status
• Fasting plasma glucose
• Haemoglobin A1c (HbA1c)
• Hepatitis B virus screening
  - Hepatitis B surface antigen (HBsAg)
  - Hepatitis B core antibody (anti-HBc)
  -  Total Ig or IgG
  - Antibody to hepatitis B surface antigen (anti-HBs)

Specific cases may require

• Pregnancy status
• Radiologic exam

Additional observations

• Diarrhoea and colitis
• Signs and symptoms of
  - Severe cutaneous adverse reactions
  - Hypersensitivity
  - New or worsening respiratory symptoms
  - Hyperglycaemia
• Signs and symptoms of noninfectious pneumonitis
  - Hypoxia
  - Cough
  - Dyspnoea
  - Interstitial infiltrates
• Signs and symptoms of infections or neoplasms
• Monitor adherence

The recommended dose modifications for management of adverse reactions

Dose adjustment recommendations for adverse reactions

- South African manufacturer recommendations

Alpelisib dose level	Dose
Starting dose	300mg, dly (2 x 150mg tablets)
First dose reduction	250mg, dly (1 x 200mg tablet and 1 x 50mg tablet)
Second dose reduction	200mg, dly (1 x 200mg tablet)
Only one dose reduction is permitted for pancreatitis If further dose reduction below 200mg, dly is required, discontinue alpelisib

- International manufacturer recommendations 

• A maximum of 2 dose reductions are recommended, after which the patient should be permanently discontinued from treatment with alpelisib. Dose reduction should be based on the worst preceding toxicity
• The clinical judgement of the treating physician, including confirmation of laboratory values if deemed necessary, should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with alpelisib

Alpelisib dose level	Dose
Starting dose	300mg, dly (2 x 150mg tablets)
First dose reduction	250mg, dly (1 x 200mg tablet and 1 x 50mg tablet)
Second dose reduction	200mg, dly (1 x 200mg tablet)
Only one dose reduction is permitted for pancreatitis

Management recommendations for hyperglycaemia

- South African manufacturer recommendations

Fasting plasma glucose (FPG)/blood glucose values1	Recommendation
Grade 1: FPG>ULN-160mg/dl or >ULN-8.9mmol/l	- No alpelisib dose adjustment required  - Initiate or intensify oral antidiabetic treatment2
Grade 2: FPG>160-250mg/dl or >8.9-13.9mmol/l	- No alpelisib dose adjustment required  - Initiate or further intensify oral antidiabetic treatment2  - If FPG does not decrease to ≤160mg/dl or 8.9mmol/l within 21 days with appropriate antidiabetic treatment, reduce alpelisib dose by 1 dose level and follow FPG value specific recommendations
Grade 3: >250-500mg/dl or >13.9-27.8mmol/l	- Interrupt alpelisib  - Initiate or intensify oral antidiabetic treatment2 and consider additional antidiabetic medications3 for 1-2 days until hyperglycaemia improves  - Administer intravenous hydration and consider appropriate treatment (e.g. intervention for electrolyte/ketoacidosis/hyperosmolar disturbances)  - If FPG decreases to ≤160mg/dl or 8.9mmol/l within 3-5 days under appropriate antidiabetic treatment, resume alpelisib at next lower dose level  - If FPG does not decrease to ≤160mg/dl or 8.9mmol/l within 3-5 days under appropriate antidiabetic treatment, consultation with a healthcare professional with expertise in the treatment of hyperglycaemia is recommended  - If FPG does not decrease to ≤160mg/dl or 8.9mmol/l within 21 days following appropriate antidiabetic treatment2, permanently discontinue alpelisib treatment
Grade 4: >500mg/dl or ≥27.8mmol/l	- Interrupt alpelisib  - Initiate or intensify appropriate antidiabetic treatment2 (e.g. intervention for electrolyte/ketoacidosis/hyperosmolar disturbances), re-check FPG within 24 hours and as clinically indicated  - If FPG decreases to ≤500mg/dl or ≤27.8mmol/l, then follow FPG value specific recommendations for grade 3. If FPG is confirmed at >500mg/dl or ≥27.8mmol/l, permanently discontinue alpelisib treatment
1 FPG/Blood Glucose/Grade levels reflect hyperglycaemia grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events)  2 Initiate applicable anti-diabetic medications, including metformin and insulin sensitizers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors), and review respective prescribing information for dosing and dose titration recommendations, including local diabetic treatment guidelines. Metformin was recommended in the SOLAR-1 trial with the following guidance: Initiate metformin 500mg once daily. Based on tolerability, metformin dose may be increased to 500mg twice daily, followed by 500mg with breakfast, and 1000mg with dinner, followed by further increase to 1000mg twice daily if needed  3 As recommended in the phase III clinical study, insulin may be used for 1-2 days until hyperglycaemia resolves. However, this may not be necessary in the majority of cases of alpelisib-induced hyperglycaemia, given the short half-life of alpelisib and the expectation of glucose levels normalising after interruption of alpelisib

- International manufacturer recommendations

• Baseline diabetic and pre-diabetic status, baseline BMI≥30 and baseline age ≥75 years have been found to be risk factors for hyperglycaemia in patients treated with alpelisib
• These risk factors were present in 74.7% of patients with any grade of hyperglycaemia and in 86.2% of patients with grade 3 or 4 hyperglycaemia

Fasting glucose (FG) values1	Recommendation
Dose modification and management should only be based on fasting glucose (plasma/blood) values
>ULN-160mg/dl or  >ULN-8.9mmol/l	- No alpelisib dose adjustment required  - Initiate or intensify oral antidiabetic treatment2
>160-250mg/dl or  >8.9-13.9mmol/l	- No alpelisib dose adjustment required  - Initiate or intensify oral antidiabetic treatment2  - If FG does not decrease to ≤160mg/dl or 8.9mmol/l within 21 days with appropriate oral antidiabetic treatment2,3, reduce alpelisib dose by 1 dose level and follow FG-value-specific recommendations
>250-500mg/dl or  >13.9-27.8mmol/l	- Interrupt alpelisib  - Initiate or intensify oral antidiabetic treatment2 and consider additional antidiabetic medicinal agents such as insulin3 for 1-2 days until hyperglycaemia resolves, as clinically indicated  - Administer intravenous hydration and consider appropriate treatment (e.g. intervention for electrolyte / ketoacidosis / hyperosmolar disturbances)  - If FG decreases to ≤160mg/dl or 8.9mmol/l within 3-5 days under appropriate antidiabetic treatment, resume alpelisib at next lower dose level  - If FG does not decrease to ≤160mg/dl or 8.9mmol/l within 3-5 days under appropriate antidiabetic treatment, consultation with a healthcare professional with expertise in the treatment of hyperglycaemia is recommended  - If FG does not decrease to ≤160mg/dl or 8.9mmol/l within 21 days following appropriate antidiabetic treatment2,3, permanently discontinue alpelisib treatment
>500mg/dl or  ≥27.8mmol/l	- Interrupt alpelisib  - Initiate or intensify appropriate antidiabetic treatment2,3 (administer intravenous hydration and consider appropriate treatment [e.g. intervention for electrolyte / ketoacidosis / hyperosmolar disturbances]), recheck within 24 hours and as clinically indicated  - If FG decreases to ≤500mg/dl or ≤27.8mmol/l, then follow FG-value-specific recommendations for <500 mg/dl  - If FG is confirmed at >500mg/dl or ≥27.8mmol/l after 24 hours, permanently discontinue alpelisib treatment
1 Fasting glucose levels reflect hyperglycaemia grading according to CTCAE Version 4.03 CTCAE = Common Terminology Criteria for Adverse Events  2 Applicable antidiabetic medicinal agents, such as metformin, SGLT2 inhibitors or insulin sensitisers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors), should be initiated and the respective prescribing information should be reviewed for dosing and dose titration recommendations, including local diabetic treatment guidelines. Metformin was recommended in the phase III clinical study with the following guidance: Metformin should be initiated at 500mg once daily. Based on tolerability, the metformin dose may be increased to 500mg twice daily, followed by 500mg with breakfast, and 1000 mg with the evening meal, followed by further increase to 1000mg twice daily if needed 3 As recommended in the phase III clinical study, insulin may be used for 1-2 days until hyperglycaemia resolves. However, this may not be necessary in the majority of cases of alpelisib-induced hyperglycaemia, given the short half-life of alpelisib and the expectation of glucose levels normalising following interruption of alpelisib

 - Schedule of fasting glucose monitoring

• Patients should be advised of the signs and symptoms of hyperglycaemia (e.g. excessive thirst, urinating more often than usual or greater amount of urine than usual, increased appetite with weight loss)

	Recommended schedule for the monitoring of fasting glucose and HbA1c levels in all patients treated with alpelisib	Recommended schedule of monitoring of fasting glucose and HbA1c levels in patients with diabetes, pre-diabetes, BMI≥30 or age ≥75 years treated with alpelisib
At screening, before initiating treatment with alpelisib	Test for fasting plasma glucose (FPG), HbA1c, and optimise the patient's level of blood glucose
After initiating treatment with alpelisib	Monitor fasting glucose at weeks 1, 2, 4, 6 and 8 after treatment start and monthly thereafter
	Monitor/self-monitor fasting glucose regularly, more frequently in the first 4 weeks and especially within the first 2 weeks of treatment, according to the instructions of a healthcare professional*	Monitor/self-monitor fasting glucose daily for the first 2 weeks of treatment. Then continue to monitor fasting glucose as frequently as needed to manage hyperglycaemia according to the instructions of a healthcare professional*
	HbA1c should be monitored after 4 weeks of treatment and every 3 months thereafter
If hyperglycaemia develops after initiating treatment with alpelisib	Monitor fasting glucose regularly, as per local standard of care and at least until fasting glucose decreases to normal levels
	During treatment with antidiabetic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks, and monitor fasting glucose according to the instructions of a healthcare professional with expertise in the treatment of hyperglycaemia
* All glucose monitoring should be performed at the physician's discretion as clinically indicated

Management recommendations for rash

- South African manufacturer recommendations

Grade 1,2	Recommendation 3
Grade 1: <10% body surface area (BSA) with active skin toxicity	- No alpelisib dose adjustment required  - Initiate topical corticosteroid treatment  - Consider adding oral antihistamine treatment to manage symptoms
Grade 2: 10-30% BSA with active skin toxicity	- No alpelisib dose adjustment required  - Initiate or intensify topical corticosteroid and oral antihistamine treatment  - Consider low-dose oral corticosteroid treatment
Grade 3 (e.g. severe rash not responsive to medical management): >30% BSA with active skin toxicity	- Interrupt alpelisib  - Initiate or intensify topical/oral corticosteroid and antihistamine treatment - Once improved to grade ≤1, then resume alpelisib at the same dose level for first occurrence of rash, or at next lower dose level, in case of second occurrence
Grade 4 (e.g. severe bullous, blistering or exfoliating skin conditions): Any % BSA associated with extensive superinfection, with intravenous antibiotics indicated; life-threatening consequences	- Permanently discontinue alpelisib
1 Grading according to CTCAE Version 5.0  2 For all grades of rash, consider consultation with a dermatologist  3 Antihistamines administered prior to rash onset may decrease incidence and severity of rash based on the SOLAR-1 trial

- International manufacturer recommendations

• Oral antihistamine administration may be considered prophylactically, at the time of initiation of treatment with alpelisib. Additionally, antihistamines are recommended to manage symptoms of rash 
• Topical corticosteroid treatment should be initiated at the first signs of rash and systemic corticosteroids should be considered for moderate to severe rashes. Based on the severity of rash, alpelisib may require dose interruption, reduction or discontinuation as described below

Grade	Recommendation
All grades	Consultation with a dermatologist should always be considered
Grade 1: <10% body surface area (BSA) with active skin toxicity	- No alpelisib dose adjustment required  - Initiate topical corticosteroid treatment  - Consider adding oral antihistamine treatment to manage symptoms - If active rash is not improved within 28 days of appropriate treatment, add a low dose systemic corticosteroid
Grade 2: 10-30% BSA with active skin toxicity	- No alpelisib dose adjustment required  - Initiate or intensify topical corticosteroid and oral antihistamine treatment  - Consider low-dose oral corticosteroid treatment  - If rash improves to grade ≤1 within 10 days, systemic corticosteroid may be discontinued
Grade 3 (e.g. severe rash not responsive to medical management): >30% BSA with active skin toxicity	- Interrupt alpelisib until rash improves to grade ≤1 - Initiate or intensify topical/systemic corticosteroid and antihistamine treatment  - Once rash improves to grade ≤1, resume alpelisib at next lower dose level
Grade 4 (e.g. severe bullous, blistering or exfoliating skin conditions): Any % BSA associated with extensive superinfection, with intravenous antibiotics indicated; life-threatening consequences	- Permanently discontinue alpelisib
1 Grading according to CTCAE Version 5.0

Management recommendations for diarrhoea

- South African manufacturer recommendations

• Severe diarrhoea, including dehydration and acute kidney injury, occurred in patients treated with alpelisib
• Most patients (58%) experienced diarrhoea during treatment with alpelisib
• Grade 3 diarrhea occurred in 7% (n=19) of patients. Among patients with grade 2 or 3 diarrhoea (n=71), the median time to onset was 46 days (range: 1-442 days)
• Dose reductions of alpelisib were required in 5.6% of patients and 2.8% of patients discontinued alpelisib due to diarrhoea
• In the 164 patients who experienced diarrhoea, antidiarrhoeal medications (e.g. loperamide) were required to manage symptoms in 63% (104/164)
• Based on the severity of the diarrhoea, alpelisib may require dose interruption, reduction or discontinuation as described below
• Patients should be advised to start antidiarrhoeal treatment, increase oral fluids and notify their healthcare provider if diarrhoea occurs while taking alpelisib

Grade1	Recommendation
Grade 1	- No alpelisib dose adjustment is required - Initiate appropriate medical therapy and monitor as clinically indicated
Grade 2	- Initiate or intensify appropriate medical therapy and monitor as clinically indicated - Interrupt alpelisib dose until recovery to grade ≤1, then resume alpelisib at same dose level
Grade 3 and 4	- Initiate or intensify appropriate medical therapy and monitor as clinically indicated - Interrupt alpelisib dose until recovery to grade ≤1, then resume alpelisib at the next lower dose level
1 Grading according to CTCAE Version 5.0

- International manufacturer recommendations

• Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with alpelisib and resolved with appropriate intervention
• 59.5% of patients (n=169) experienced diarrhoea during treatment with alpelisib
• Grade 3 diarrhoea occurred in 7% (n=20) of patients with no reported cases of grade 4
• Among patients with grade 2 or 3 diarrhoea (n=76), the median time to onset was 50 days (range: 1-954 days)
• Dose reductions of alpelisib were required in 5.6% of patients and 2.8% of patients discontinued alpelisib due to diarrhoea
• In the 169 patients who experienced diarrhoea, antidiarrhoeal medications (e.g. loperamide) were required to manage symptoms in 64.5% (109/169)
• Based on the severity of the diarrhoea, alpelisib may require dose interruption, reduction or discontinuation as described below
• Patients should be advised to start antidiarrhoeal treatment, increase oral fluids and notify their physician if diarrhoea occurs while taking alpelisib

Grade1	Recommendation
Grade 1	- No alpelisib dose adjustment is required - Initiate appropriate medical therapy and monitor as clinically indicated
Grade 2	- Interrupt alpelisib dose - Initiate or intensify appropriate medical therapy and monitor as clinically indicated - If diarrhoea improves to grade ≤1, then resume alpelisib at same dose level - If diarrhoea recurs as grade ≥2, interrupt alpelisib dose until improvement to grade ≤1, then resume alpelisib at the next lower dose level
Grade 32	- Interrupt alpelisib dose - Initiate or intensify appropriate medical therapy and monitor as clinically indicated - If diarrhoea improves to grade ≤1, then resume alpelisib at the next lower dose level
Grade 4	- Permanently discontinue alpelisib
1 Grading according to CTCAE Version 5.0  2 Patients should additionally be managed according to local standard of care, including electrolyte monitoring, administration of antiemetics and antidiarrhoeal medicinal products and/or fluid replacement and electrolyte supplements, as clinically indicated

Management recommendations for other toxicities

- South African manufacturer recommendations

Grade1	Recommendation
Grade 1 or 2	- No alpelisib dose adjustment is required - Initiate appropriate medical therapy and monitor as clinically indicated2,3
Grade 3	- Interrupt alpelisib dose until recovery to grade ≤1, then resume alpelisib at the next lower dose level2
Grade 4	- Permanently discontinue alpelisib
1 Grading according to CTCAE Version 5.0  2 For grade 2 and 3 pancreatitis, interrupt alpelisib dose until recovery to grade <2 and resume at next lower dose level. Only one dose reduction is permitted. If toxicity recurs, permanently discontinue alpelisib treatment  3 For grade 2 total bilirubin elevation, interrupt alpelisib dose until recovery to grade ≤1 and resume at the same dose if resolved in ≤14 days or resume at the next lower dose level if resolved in >14 days

- International manufacturer recommendations

Grade 1	Recommendation
Grade 1 or 2	- No alpelisib dose adjustment is required - Initiate appropriate medical therapy and monitor as clinically indicated2,3
Grade 3	- Interrupt alpelisib dose until improvement to grade ≤1, then resume alpelisib at the next lower dose level2
Grade 4	- Permanently discontinue alpelisib
1 Grading according to CTCAE Version 5.0  2 For grade 2 and 3 pancreatitis, interrupt alpelisib dose until improvement to grade ≤1 and resume at next lower dose level. Only one dose reduction is permitted. If toxicity recurs, permanently discontinue alpelisib treatment 3 For grade 2 total bilirubin elevation, interrupt alpelisib dose until recovery to grade ≤1 and resume at the same dose if resolved in ≤14 days or resume at the next lower dose level if resolved in >14 days

Hypersensitivity

• Serious hypersensitivity reactions (including anaphylactic reaction and anaphylactic shock), manifested by symptoms including, but not limited to, dyspnoea, flushing, rash, fever or tachycardia, were reported in patients treated with alpelisib in clinical studies
• Alpelisib should be permanently discontinued and should not be re-introduced in patients with serious hypersensitivity reactions. Appropriate treatment should be promptly initiated

Severe cutaneous reactions

• Severe cutaneous reactions have been reported with alpelisib. In the phase III clinical study, Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in 1 (0.4%) and 3 (1.1%) patients, respectively
• Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in the post-marketing setting
• Alpelisib treatment should not be initiated in patients with a history of severe cutaneous reactions
• Patients should be advised of the signs and symptoms of severe cutaneous reactions (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash)
• If signs or symptoms of severe cutaneous reactions are present, alpelisib should be interrupted until the aetiology of the reaction has been determined
• A consultation with a dermatologist is recommended
• If a severe cutaneous reaction is confirmed, alpelisib should be permanently discontinued
• Alpelisib should not be reintroduced in patients who have experienced previous severe cutaneous reactions
• If a severe cutaneous reaction is not confirmed, alpelisib may require treatment interruption, dose reduction or treatment discontinuation

Pneumonitis

• Pneumonitis, including serious cases of pneumonitis/acute interstitial lung disease, have been reported in alpelisib-treated patients in clinical studies
• Patients should be advised to report promptly any new or worsening respiratory symptoms
• In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, alpelisib treatment should be interrupted immediately and the patient should be evaluated for pneumonitis
• A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, cough, dyspnoea, or interstitial infiltrates on radiological examination and in whom infectious, neoplastic and other causes have been excluded by means of appropriate investigations
• Alpelisib should be permanently discontinued in all patients with confirmed pneumonitis

Osteonecrosis of the jaw

• Caution should be exercised when alpelisib and bisphosphonates or RANK-ligand inhibitors (e.g. denosumab) are used either simultaneously or sequentially
• Alpelisib treatment should not be initiated in patients with ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates/denosumab
• Patients should be advised to promptly report any new or worsening oral symptoms (such as dental mobility, pain or swelling, non-healing of mouth sores, or discharge) during treatment with alpelisib
• In patients who develop osteonecrosis of the jaw, standard medical management should be initiated

Alpelisib is an α-specific class I phosphatidylinositol3kinase (PI3Kα) inhibitor. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and AKT-signalling, cellular transformation and the generation of tumours in in vitro and in vivo models. In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets including AKT, and showed activity in cell lines harbouring a PIK3CA mutation. In vivo, alpelisib inhibited the PI3K/AKT signalling pathway and reduced tumour growth in xenograft models, including models of breast cancer. PI3K inhibition by alpelisib treatment has been shown to induce an increase in oestrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased anti-tumour activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines. The PI3K/AKT signalling pathway is responsible for glucose homeostasis, and hyperglycaemia is an expected on-target adverse reaction of PI3K inhibition.

Film coated tablet 50mg & 200mg

• Pivikto multipack (Novartis) originator

Film coated tablet 150mg

• Pivikto (Novartis) originator

Film coated tablet 200mg

• Pivikto (Novartis) originator