Drugs List

Therapeutic Indications

Uses

Treatment of unresectable or metastatic melanoma with BRAF V600 mutation

Monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma.

Contraindications

Children under 18 years
Breastfeeding
Long QT syndrome
Pregnancy
QTc interval greater than or equal to 500 msec
Torsade de pointes

Precautions and Warnings

Concurrent radiotherapy
Family history of long QT syndrome
History of radiotherapy
History of treatment with anthracyclines
Electrolyte imbalance
History of torsade de pointes
Moderate hepatic impairment
RAS mutation associated cancer
Severe renal impairment

Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Concurrent radiotherapy may increase risk of serious adverse effects
Confirm BRAF V600 mutation status of tumour prior to treatment
CT scan recommended prior to and every 6 months during treatment
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Anal examination advised before, during and at end of treatment
Examine head and neck prior to and every 3 months during treatment
Monitor ECG before initiating, at 1 month and after dose modifications
Monitor electrolytes before initiating,at 1 month & after dose modification
Monitor hepatic function before initiating and at monthly intervals
Monitor QT interval before and during treatment
Monitor serum creatinine prior to and during treatment
Pelvic examination advised before, during and at end of treatment
Monitor closely patient with pre-existing renal impairment
Monitor ECG more frequently in patients with moderate hepatic impairment
Monitor for skin lesions prior to, during and for 6 months after treatment
Monitor ophthalmic function
Advise patient to report unexplained nausea,vomiting,abdominal pain
Consider pancreatitis in patients with unexplained abdominal pain
Discontinue/interrupt therapy/reduce dose if Dupuytren's contracture occurs
Discontinue/interrupt therapy/reduce dose if plantar fascial fibromatosis
Discontinue permanently if QTc > 500 msec and is > 60 msec above baseline
Discontinue permanently if severe hypersensitivity reactions occur
Discontinue permanently if severe skin reaction occurs
Interrupt treatment if QTc exceeds 500msec and consider dose modification
Advise patient not to take St John's wort concurrently
Female: Contraception required during and for 6 months after treatment
Advise patient on appropriate sun protection methods
Advise patient that photosensitivity possible
Advise patient to inform physician of any skin changes immediately

ECG monitoring should take place in all patients before treatment, after 1 month of treatment and after dose modification. Patients with moderate to severe hepatic impairment should have ECG monitoring every month for the first 3 months and then every 3 months thereafter or more often if clinically indicated.

An increased risk of malignancies may be seen when vemurafenib is administered to patients with RAS mutations. Careful consideration of the benefits and risks must be carried out before administering vemurafenib to patients with prior or concurrent cancer associated with RAS mutations.

Cases of pancreatitis have been reported in patients treated with vemurafenib. Investigate unexplained abdominal pain, including measurements of serum amylase and lipase. Closely monitor patients when re-starting treatment after an episode of pancreatitis.

Radiation recall and sensitization have been reported in patients treated with vemurafenib and prior, concurrent or subsequent radiation. Most cases were cutaneous but some cases involving visceral organs have had fatal outcomes.

In the event the patient develops cutaneous Squamous cell carcinoma it is recommended to continue with vemurafenib without modifying the dose.

Pregnancy and Lactation

Pregnancy

Vemurafenib is contraindicated in pregnancy.

At the time of writing there is no published data on the use of vemurafenib in pregnant women.

In animal studies vemurafenib was found to cross the placenta, however rat and rabbit studies showed no teratogenic effects on the embryo or foetus.

Vemurafenib should only be administered if the benefits to the mother outweighs the risks to the foetus.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Vemurafenib is contraindicated in breastfeeding.

It is unknown if vemurafenib is excreted into breast milk. A risk to neonates cannot be excluded.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Actinic keratosis
Acute interstitial nephritis
Acute tubular necrosis
Alopecia
Anaphylaxis
Arthralgia
Arthritis
Asthenia
Back pain
Basal cell carcinoma
Constipation
Cough
Decreased appetite
Diarrhoea
Dizziness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dry skin
Dupuytren's contracture
Dysgeusia
Erythema
Erythema nodosum
Extremity pain
Facial nerve paresis
Fatigue
Folliculitis
Gamma glutamyl transferase (GGT) increased
Headache
Hepatic damage
Hyperkeratosis
Hypersensitivity reactions
Increase in alkaline phosphatase
Increase in serum ALT/AST
Iritis
Keratoacanthoma
Keratosis
Leukaemia
Maculopapular rash
Malignant melanoma
Musculoskeletal pain
Myalgia
Nausea
Neutropenia
Palmar-Plantar Erythrodysaesthesia syndrome
Pancreatitis
Panniculitis
Peripheral neuropathy
Peripheral oedema
Photosensitivity
Plantar fibromatosis
Prolongation of QT interval
Pruritus
Pyrexia
Radiation cystitis
Radiation esophagitis
Radiation hepatitis
Radiation necrosis
Radiation pneumonitis
Radiation proctitis
Radiation recall dermatitis
Rash
Retinal vein occlusion
Sarcoidosis
Serum bilirubin increased
Serum creatinine increased
Skin papilloma
Squamous cell carcinoma
Stevens-Johnson syndrome
Sunburn
Toxic epidermal necrolysis
Uveitis
Vasculitis
Vomiting
Weight loss

Presentation

Oral formulations of vemurafenib.

Drugs List

Therapeutic Indications

Uses

Treatment of unresectable or metastatic melanoma with BRAF V600 mutation

Monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma.

Dosage

Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Before administering vemurafenib, patients must have a confirmation of tumour BRAF V600 mutation using a validated test.

Adults

Elderly

Additional Dosage Information

Contraindications

Children under 18 years
Breastfeeding
Long QT syndrome
Pregnancy
QTc interval greater than or equal to 500 msec
Torsade de pointes

Precautions and Warnings

Concurrent radiotherapy
Family history of long QT syndrome
History of radiotherapy
History of treatment with anthracyclines
Electrolyte imbalance
History of torsade de pointes
Moderate hepatic impairment
RAS mutation associated cancer
Severe renal impairment

Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Concurrent radiotherapy may increase risk of serious adverse effects
Confirm BRAF V600 mutation status of tumour prior to treatment
CT scan recommended prior to and every 6 months during treatment
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Anal examination advised before, during and at end of treatment
Examine head and neck prior to and every 3 months during treatment
Monitor ECG before initiating, at 1 month and after dose modifications
Monitor electrolytes before initiating,at 1 month & after dose modification
Monitor hepatic function before initiating and at monthly intervals
Monitor QT interval before and during treatment
Monitor serum creatinine prior to and during treatment
Pelvic examination advised before, during and at end of treatment
Monitor closely patient with pre-existing renal impairment
Monitor ECG more frequently in patients with moderate hepatic impairment
Monitor for skin lesions prior to, during and for 6 months after treatment
Monitor ophthalmic function
Advise patient to report unexplained nausea,vomiting,abdominal pain
Consider pancreatitis in patients with unexplained abdominal pain
Discontinue/interrupt therapy/reduce dose if Dupuytren's contracture occurs
Discontinue/interrupt therapy/reduce dose if plantar fascial fibromatosis
Discontinue permanently if QTc > 500 msec and is > 60 msec above baseline
Discontinue permanently if severe hypersensitivity reactions occur
Discontinue permanently if severe skin reaction occurs
Interrupt treatment if QTc exceeds 500msec and consider dose modification
Advise patient not to take St John's wort concurrently
Female: Contraception required during and for 6 months after treatment
Advise patient on appropriate sun protection methods
Advise patient that photosensitivity possible
Advise patient to inform physician of any skin changes immediately

ECG monitoring should take place in all patients before treatment, after 1 month of treatment and after dose modification. Patients with moderate to severe hepatic impairment should have ECG monitoring every month for the first 3 months and then every 3 months thereafter or more often if clinically indicated.

An increased risk of malignancies may be seen when vemurafenib is administered to patients with RAS mutations. Careful consideration of the benefits and risks must be carried out before administering vemurafenib to patients with prior or concurrent cancer associated with RAS mutations.

Cases of pancreatitis have been reported in patients treated with vemurafenib. Investigate unexplained abdominal pain, including measurements of serum amylase and lipase. Closely monitor patients when re-starting treatment after an episode of pancreatitis.

Radiation recall and sensitization have been reported in patients treated with vemurafenib and prior, concurrent or subsequent radiation. Most cases were cutaneous but some cases involving visceral organs have had fatal outcomes.

In the event the patient develops cutaneous Squamous cell carcinoma it is recommended to continue with vemurafenib without modifying the dose.

Pregnancy and Lactation

Pregnancy

Vemurafenib is contraindicated in pregnancy.

At the time of writing there is no published data on the use of vemurafenib in pregnant women.

In animal studies vemurafenib was found to cross the placenta, however rat and rabbit studies showed no teratogenic effects on the embryo or foetus.

Vemurafenib should only be administered if the benefits to the mother outweighs the risks to the foetus.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Vemurafenib is contraindicated in breastfeeding.

It is unknown if vemurafenib is excreted into breast milk. A risk to neonates cannot be excluded.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

Advise patient if a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time.

Advise patients not to take St John's work concurrently.

Advise patient to report any skin changes immediately.

Advise patients to report unexplained nausea, vomiting or abdominal pain.

Advise patient that photosensitivity is possible.

Advise patient on appropriate sun protection methods.

Advise female patients that contraception is required during and for 6 months after treatment.

Advise patients that their ability to drive/operate machinery may be affected by side effects.

Side Effects

Actinic keratosis
Acute interstitial nephritis
Acute tubular necrosis
Alopecia
Anaphylaxis
Arthralgia
Arthritis
Asthenia
Back pain
Basal cell carcinoma
Constipation
Cough
Decreased appetite
Diarrhoea
Dizziness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dry skin
Dupuytren's contracture
Dysgeusia
Erythema
Erythema nodosum
Extremity pain
Facial nerve paresis
Fatigue
Folliculitis
Gamma glutamyl transferase (GGT) increased
Headache
Hepatic damage
Hyperkeratosis
Hypersensitivity reactions
Increase in alkaline phosphatase
Increase in serum ALT/AST
Iritis
Keratoacanthoma
Keratosis
Leukaemia
Maculopapular rash
Malignant melanoma
Musculoskeletal pain
Myalgia
Nausea
Neutropenia
Palmar-Plantar Erythrodysaesthesia syndrome
Pancreatitis
Panniculitis
Peripheral neuropathy
Peripheral oedema
Photosensitivity
Plantar fibromatosis
Prolongation of QT interval
Pruritus
Pyrexia
Radiation cystitis
Radiation esophagitis
Radiation hepatitis
Radiation necrosis
Radiation pneumonitis
Radiation proctitis
Radiation recall dermatitis
Rash
Retinal vein occlusion
Sarcoidosis
Serum bilirubin increased
Serum creatinine increased
Skin papilloma
Squamous cell carcinoma
Stevens-Johnson syndrome
Sunburn
Toxic epidermal necrolysis
Uveitis
Vasculitis
Vomiting
Weight loss

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: March 2016

Reference Sources

Summary of Product Characteristics: Zelboraf 240mg film-coated tablets. Roche Products Limited. Revised August 2018.

MHRA Drug Safety Update November 2015
Available at: https://www.mhra.gov.uk
Last accessed: 17 November 2015

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 09 March 2016