Prescribing information

 

   

Helping patients on their TAFINLAR + MEKINIST treatment journey

 

Dose reduction, treatment interruption or treatment discontinuation may be required to manage adverse reactions associated with TAFINLAR + MEKINIST treatment1,2

When a patient’s adverse events are effectively managed, then a return to the starting dose, via dose escalation, can be considered in the same step wise approach done for dose reductions1,2

Specific guidelines are available on the management of pyrexia, a common adverse event of TAFINLAR + MEKINIST treatment1,2

 

This key information on managing side effects that may occur while patients are being treated with TAFINLAR + MEKINIST may be helpful when discussing this with your patients.

 

Adverse events associated with TAFINLAR + MEKINIST are well-established and are generally similar in both the metastatic and adjuvant settings3,4

 

TAFINLAR, in combination with MEKINIST, is indicated for:

  • Adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.1,2
  • Treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.1,2

 

Whilst TAFINLAR + MEKINIST is likely to cause patients to experience some side effects, it has a well-established side effect profile which is generally consistent across the metastatic and adjuvant settings.3,4

The management of adverse events associated with TAFINLAR + MEKINIST treatment may require dose reduction, treatment interruption or treatment discontinuation.1,2

 

Pills icon.

Two TAFINLAR capsule strengths (50 mg and 75 mg) and two MEKINIST tablet strengths (0.5 mg and 2 mg) are available to manage dose modifications

 

Dose modification schedule based on the grade of adverse events excluding pyrexia1,2

GRADE (CTC-AE)* Recommended TAFINLAR dose modification Recommended MEKINIST dose modification 
Grade 1 or Grade 2 (tolerable) Continue treatment and monitor as clinically indicated Continue treatment and monitor as clinically indicated
Grade 2 (intolerable) or Grade 3 Interrupt therapy until toxicity is Grade 0–1 and reduce by one dose level when resuming therapy Interrupt therapy until toxicity is Grade 0–1 and reduce by one dose level when resuming therapy
Grade 4 Discontinue permanently, or interrupt therapy until Grade 0–1 and reduce by one dose level when resuming therapy Discontinue permanently, or interrupt therapy until Grade 0–1 and reduce by one dose level when resuming therapy

*The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE): Grade 1: Mild; intervention not indicated. Grade 2: Moderate; minimal, local or non-invasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated. Grade 4: Life-threatening consequences; urgent intervention indicated.

 

Recommended dose level reductions1,2

Dose level TAFINLAR dose MEKINIST dose
Starting dose 150 mg twice daily 2 mg once daily
1st dose reduction 100 mg twice daily 1.5 mg once daily
2nd dose reduction 75 mg twice daily 1 mg once daily
3rd dose reduction 50 mg twice daily 1 mg once daily
  Dose adjustment of TAFINLAR <50 mg twice daily is not recommended Dose adjustment of MEKINIST <1 mg once daily is not recommended

 

Dose modification for only one of the two treatments

TAFINLAR and MEKINIST should be simultaneously dose reduced, interrupted, or discontinued. Exceptions, where dose modifications are necessary for only one of the two treatments, are shown in the table below.1,2

 

Cases where dose modifications are necessary for only one of the two treatments1,2

Modification of TAFINLAR dose only Modification of MEKINIST dose only
  • Uveitis
  • RAS-associated non-cutaneous malignancies
  • RVO and RPED
  • LVEF reduction
  • Interstitial lung disease/pneumonitis

LVEF, left ventricular ejection fraction; RPED, retinal pigment epithelial detachment; RVO, retinal vein occlusion.

See the TAFINLAR and MEKINIST SPCs for further information on dose adjustments.

Dose modifications or interruptions are not recommended for incidences of cutaneous squamous-cell carcinoma or new primary melanoma.1

When a patient’s side effects are effectively managed, then a return to the starting dose via dose re-escalation can be considered in the same step wise approach as for dose reductions.1,2

 

Dose adjustments in special populations1,2

Children and adolescents (<18 years) Children and adolescents (<18 years) icon.
  • The safety and efficacy of TAFINLAR + MEKINIST have not yet been established in children and adolescents (<18 years)
Elderly Elderly icon.
  • No adjustment of the initial dose of TAFINLAR or MEKINIST is required in patients >65 years of age
  • More frequent dose adjustments of MEKINIST may be required in patients >65 years of age
Renal impairment Renal impairment icon.
  • Mild to moderate: No dose adjustment of TAFINLAR or MEKINIST is required
  • Severe: Use with caution. There are no clinical data for TAFINLAR or MEKINIST in patients with severe renal impairment and the potential need for dose adjustment cannot be determined
Hepatic impairment Hepatic impairment icon.
  • Mild: No dose adjustment of TAFINLAR or MEKINIST is required
  • Moderate to severe: Use with caution. There are no clinical data for TAFINLAR or MEKINIST in patients with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined

Pyrexia was the most common adverse event observed in Phase II and III clinical trials of TAFINLAR + MEKINIST.3-6

~50% of first occurrences happen in the first month of therapy and the majority of cases are mild to moderate.1,5,6 In the metastatic melanoma setting, the median duration of the first pyrexia event was three days (COMBI-d trial).7 In the adjuvant setting, the median duration of the first pyrexia event was two days (COMBI-APlus trial)6

During clinical trials, the majority of pyrexia events were mild or moderate (Grade 1 or 2).*3-6

Analysis of pyrexia in patients treated with TAFINLAR + MEKINIST in the COMBI-APlus clinical trial**6 

Management of pyrexia icon 32%

32% (178 of 552) did not experience a pyrexia event6

Management of pyrexia icon 44%

44% (166 of 374) experienced 1 or 2 occurrences of pyrexia events6

Management of pyrexia icon 4%

4% (15 of 374) experienced Grade 3 events and 1.6% (6 of 374) experienced Grade 4 events6

Management of pyrexia icon 2.4%

Only 2.4% (13 of 552) discontinued treatment with TAFINLAR or MEKINIST due to pyrexia6

 

*Pyrexia was analysed from the following clinical trials in melanoma and in metastatic non-small cell lung cancer (NSCLC): Registrational Phase II trial (NCT01336634) in metastatic non-small cell lung cancer (n=82); COMBI-AD in resected stage III melanoma (n=435); COMBI-d in unresectable or metastatic melanoma (n=209); COMBI-v in unresectable or metastatic melanoma (n=350).5 Pyrexia was also analysed in the primary analysis of the COMBI-APlus trial (NCT03551626) in resected stage III melanoma (n=552).6

**COMBI-APlus is an open-label, Phase IIIb trial evaluating an adapted pyrexia management algorithm in patients with high-risk resected stage III BRAF V600E/K–mutant melanoma treated with up to 12 months of adjuvant TAFINLAR + MEKINIST.6

 

Guidance for managing pyrexia in patients receiving TAFINLAR + MEKINIST

Patients may respond well to dose interruption (TAFINLAR when used as monotherapy, and both TAFINLAR + MEKINIST when used in combination) and supportive care for management of pyrexia, allowing later re-initiation of treatment.1,2,6

The diagram below outlines the recommended approach to managing a pyrexia event that the healthcare team who manages a patient’s care should be aware of.

Management of pyrexia: Interrupt Manage Restart graphic.

In patients with melanoma, adverse events in the adjuvant setting (COMBI-AD trial) and metastatic setting (COMBI-v and COMBI-d trials)4,5 were similar and the most common adverse events observed with TAFINLAR + MEKINIST in Phase III studies (occurring with an all-Grades incidence of ≥20%) included: pyrexia, chills, fatigue, headache, nausea, vomiting, diarrhoea, arthralgia and rash.4,5

Further information on managing side effects

For more information on potential side effects and how to manage them in patients receiving TAFINLAR + MEKINIST please refer to the TAFINLAR + MEKINIST SPCs.1,2

SPC for TAFINLAR

SPC for MEKINIST

Practical advice for patients on managing side effects can be found here.

 

Always encourage your patients to carefully read the Patient Information Leaflets (PILs) in their TAFINLAR and MEKINIST packs before starting treatment, as they contain important information for them.1,2

PIL for Tafinlar

PIL for Mekinist

Additional information is also available from your Novartis representative who can provide you with a comprehensive healthcare professional brochure about TAFINLAR + MEKINIST.

Click here to preview and request a guide on pyrexia, the most common side effect related to treatment with TAFINLAR + MEKINIST.1,2

References

  1. TAFINLAR (dabrafenib) Summary of Product Characteristics.
  2. MEKINIST (trametinib) Summary of Product Characteristics.
  3. Robert C et al. N Engl J Med 2019;381:626–636.
  4. Long GV et al. N Engl J Med 2017;377:1813–1823.
  5. Robert C, et al. Presented at ESMO 2019; 27 September–1 October, Barcelona, Spain.
  6. Atkinson V, et al. Poster 9525. Presented at ASCO 2021.
  7. Long GV et al. N Engl J Med 2014;371:1877–1888.
  8. Welsh SJ, Corrie PG. Ther Adv Med Oncol 2015;1–15.
  9. Common Terminology Criteria for Adverse Events (CTCAE) V4.0.
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UK | February 2022 | 122588
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Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Novartis via [email protected] or online through the pharmacovigilance intake (PVI) tool at www.report.novartis.com
If you have a question about the product, please contact Medical Information on 01276 698370 or by email at [email protected]