Symdeko is a combination of two drugs Tezacaftor and Ivacaftor approved for the treatment of patients with cystic fibrosis with at least two mutations as mentioned below.

Tezacaftor and ivacaftor Uses:

• Cystic fibrosis:

  • Treatment of patients with cystic fibrosis who are:
    • ≥6 years of age
    • homozygous for the F508del mutation or
    • having at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene i.e responsive to tezacaftor/ivacaftor on the basis of in vitro data and/or clinical evidence.

Note: CFTR gene mutations that produce CFTR protein and are responsive to tezacaftor/ivacaftor are listed below:

• A455E,
• A1067T,
• D110E,
• D110H,
• D579G,
• D1152H,
• D1270N,
• E56K,
• E193K,
• E831X,
• F1052V,
• F1074L,
• F508del (two copies of mutation or at least 1 copy of a responsive mutation),
• K1060T,
• L206W,
• P67L,
• R74W,
• R1070W,
• R117C,
• R347H,
• R352Q,
• 51070W,
• S945L,
• S977F,
• 711+3A→G,
• 2789+5G→A,
• 3272-26A→G,
• 3849+10kbC→T.

Tezacaftor and Ivacaftor (Symdeko) Dose in Adults

Note: Symdeko is supplied as co-packaged:

• Yellow tablets tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination  and
• Light blue tablets ivacaftor 150 mg .

Tezacaftor and Ivacaftor (Symdeko) Dose in the treatment of Cystic fibrosis:

• Oral: Tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening, approximately 12 hours apart.

• Missed dose:

  • Take the dose as soon as possible, if a dose is missed ≤6 hours of the usual time it is taken.
  • if >6 hours have passed since the missed dose, skip the missed dose and resume the normal dosing schedule.

• Tezacaftor and Ivacaftor (Symdeko) Dosage adjustment with concomitant medications:

  • Coadministration with moderate CYP3A inhibitors (eg, erythromycin, fluconazole):

    • On day 1, administer tezacaftor 100 mg/ivacaftor 150 mg once per day in the morning, and
    • on day 2, administer ivacaftor 150 mg once per day in the morning; continue this regimen with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg on alternate days in the morning; the dose of ivacaftor 150 mg at evening should not be given.

  • Coadministration with strong CYP3A inhibitors (eg, clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole):

    • On day 1, administer tezacaftor 100 mg/ivacaftor 150 mg once per day in the morning.
    • do not administer any tablets on days 2 and 3;
    • on day 4, administer tezacaftor 100 mg/ivacaftor 150 mg once per day in the morning.
    • Continue dosing with tezacaftor 100 mg/ivacaftor 150 tablets twice a week, administered almost 3 to 4 days apart;
    • the dose of ivacaftor 150 mg in the evening should not be administered.

Tezacaftor and Ivacaftor (Symdeko) Dose in Childrens

Note: Symdeko is marketed as two separate products packaged together:

• tezacaftor/ivacaftor tablets in a fixed-dose combination and
• ivacaftor tablets;
• use caution when selecting dosage form;
• multiple strengths are available.

Tezacaftor and Ivacaftor (Symdeko) Dose in the treatment of Cystic fibrosis:

• Children ≥6 years to <12 years weighing <30 kg:

  • Oral: Tezacaftor 50 mg/ivacaftor 75 mg (1 tablet) in the morning and ivacaftor 75 mg in the evening, approximately 12 hours apart.

• Children ≥6 years to <12 years weighing ≥30 kg, Children ≥12 years, and Adolescents:

  • Oral: Tezacaftor 100 mg/ivacaftor 150 mg (1 tablet) in the morning and ivacaftor 150 mg in the evening, approximately 12 hours apart.

  • Missed dose:

    • Take the dose as soon as possible, if a dose is missed ≤6 hours of the usual time it is taken;
    • if >6 hours have passed since the missed dose, skip the missed dose and resume the normal dosing schedule.

• Dosing adjustment with concomitant medications:

  • Coadministration with moderate CYP3A inhibitors (eg, erythromycin, fluconazole):

    • Children ≥6 years to <12 years weighing <30 kg:

      • An alternating schedule is necessary;
      • on day 1, administer tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning, and
      • on day 2, administer ivacaftor 75 mg only once daily in the morning;
      • continue this dosing schedule with tezacaftor 50 mg/ivacaftor 75 mg or ivacaftor 75 mg on alternate days in the morning; no evening dose of ivacaftor 75 mg should be administered on any day.

    • Children ≥6 years to <12 years weighing ≥30 kg, Children ≥12 years, and Adolescents:

      • An alternating schedule is necessary;
      • on day 1, administer tezacaftor 100 mg/ivacaftor 150 mg once in a day in the morning, and
      • on day 2, administer ivacaftor 150 mg only once daily in the morning;
      • continue this dosing schedule with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg on alternate days in the morning; no evening dose of ivacaftor 150 mg should be administered on any day.

  • Coadministration with strong CYP3A inhibitors (eg, clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole):

    • Children ≥6 years to <12 years weighing <30 kg:

    • Twice-weekly schedule:
      • On day 1, administer tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning;
      • do not administer any tablets on days 2 and 3;
      • on day 4, administer tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning.
      • Continue dosing with tezacaftor 50 mg/ivacaftor 75 tablets twice a week, administered approximately 3 to 4 days apart;
      • no evening dose of ivacaftor 75 mg should be administered on any day.

    • Children ≥6 years to <12 years weighing ≥ 30 kg, Children ≥12 years, and Adolescents:

      • Twice-weekly schedule:
      • On day 1, administer tezacaftor 100 mg/ivacaftor 150 mg once per day in the morning.
      • do not administer any tablets on days 2 and 3;
      • on day 4, administer tezacaftor 100 mg/ivacaftor 150 mg once per day in the morning.
      • Continue dosing with tezacaftor 100 mg/ivacaftor 150 tablets twice a week, administered approximately 3 to 4 days apart;
      • no evening dose of ivacaftor 150 mg should be administered on any day.

Pregnancy Risk Category: B3

• Ivacaftor passes the placental barrier
• For more information, refer to the ivacaftor Monograph.

Use of ivacaftor or zacaftor during lactation

• Ivacaftor can be found in breast milk (Trimble 2018, 2018); the excretion of Tezacaftor has not been determined.
• Consider these factors when deciding whether to breastfeed during therapy:
  • The risk of infant exposure
  • The benefits of breastfeeding your infant
  • The mother can reap the benefits of treatment.
  • For more information, refer to the ivacaftor Monograph.

Tezacaftor and Ivacaftor (Symdeko) Dose in Kidney Disease:

• CrCl >30 mL/minute:

  • No  adjustment in dosage is necessary.

• CrCl ≤30 mL/minute:

  • There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

• ESRD:

  • There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

Tezacaftor and Ivacaftor (Symdeko) Dose in Liver disease:

• Hepatic impairment prior to treatment initiation:

  • Mild impairment (Child-Pugh class A):

    • No adjustment in dosage is necessary.

  • Moderate impairment (Child-Pugh class B):

    • Tezacaftor 100 mg/ivacaftor 150 mg once per day in the morning.
    • The dose of ivacaftor 150 mg in the evening should not be administered.

  • Severe impairment (Child-Pugh class C):

    • Tezacaftor 100 mg/ivacaftor 150 mg once per day in the morning (or less frequently).
    • The dose of ivacaftor 150 mg in the evening should not be administered.

• Hepatotoxicity during treatment:

  • ALT or AST >5 × ULN without concomitant elevated bilirubin:

    • Temporarily discontinue tezacaftor/ivacaftor;
    • may resume if elevated transaminases resolved and
    • after assessing benefits versus risks of continued treatment.

  • ALT or AST >3 × ULN with concomitant bilirubin >2 × ULN:

    • Temporarily discontinue tezacaftor/ivacaftor;
    • may resume if elevated transaminases resolved and
    • after assessing benefits versus risks of continued treatment.

Common Side Effects of Tezacaftor and Ivacaftor (Symdeko):

• Central nervous system:

  • Headache

Less Common Side Effects of Tezacaftor and Ivacaftor (Symdeko):

• Central nervous system:

  • Dizziness

• Gastrointestinal:

  • Nausea

• Respiratory:

  • Paranasal sinus congestion

Contraindications to Tezacaftor and Ivacaftor (Symdeko):

Hypersensitivity to ivacaftor or tezacaftor or any other component of the formulation

Warnings and precautions

• Cataracts

  • Children who received treatment with ivacaftor/tezacaftor have reported noncongenital lenses opacities and cataracts.
  • Other risk factors, such as corticosteroid use and radiation exposure, were also present in certain cases, but there is no way to rule out a potential risk from tezacaftor/ivacaftor.
  • Patients with such conditions are advised to have follow-up and Baseline ophthalmological exams.

• CNS effects

  • Dizziness can cause dizziness which may lead to impairment of mental or physical abilities.
  • Patients must be educated and counseled on how to perform tasks that require mental alertness (eg driving, operating machinery).

• Hepatic effects

  • May increase liver transaminases.
  • Monitor ALT, AST and bilirubin at baseline every 3 months during the first year of therapy and annually thereafter.
  • Patients with elevated liver transaminases may require increased monitoring.
  • Temporarily stop treatment if ALT/AST >5x ULN, or ALT/AST >3x ULN with concomitant Bilirubin >2x ULN.
  • Consider the risks and benefits of resuming treatment after transaminase elevations have been resolved.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious; dose adjustment is recommended for patients with moderate to severe (Childugh class B orC) impairment.

• Renal impairment

  • Patients with severe impairment (CrCl =30mL/minute or ESRD) should be cautious.

Tezacaftor and ivacaftor: Drug Interaction

Monitoring parameters:

• CF mutation test (prior to therapy if the genotype is unknown);
• ophthalmological examinations (baseline and follow-up in pediatric patients);
• ALT and AST (baseline, every 3 months for the first year of therapy, and annually thereafter; increased monitoring may be necessary for patients with a history of elevated hepatic transaminases or bilirubin).

How to administer Tezacaftor and Ivacaftor (Symdeko)?

• Swallow the tablets whole.
• Administer with fat-containing food (eg, eggs, butter, oils, cheese, nuts, peanut butter, meats, whole-milk dairy products).
• Food or drink containing grapefruit or Seville oranges should be avoided.

Mechanism of action of Tezacaftor and Ivacaftor (Symdeko):

Tezacaftor

• It facilitates the cellular processing of select mutant and normal forms of CFTR (including F508delCFTR), to increase the amount of mature CFTR protein delivered directly to the cell's surface.

Ivacaftor:

• This is a CFTR Potentiator, which increases chloride transport by increasing the channel-open probability (or gating), of the CFTR protein at cell surface.

Absorption:

• Ivacaftor and tezacaftor: Variable; increased (by almost 3-fold) when administered with fatty foods.

Protein binding:

• Ivacaftor: ~99%; primarily to alpha -acid glycoprotein and albumin
• Tezacaftor: ~99%; primarily to albumin

Metabolism:

• Ivacaftor:
  • Hepatic metabolism is extensive via CYP3A and CYP3A5; forming 2 major metabolites which are (M1 [active; 1/6 potency] and M6 [inactive])
• Tezacaftor:
  • Hepatic metabolism is extensive via CYP3A and CYP3A5; forming 3 major metabolites which are (M1 and M2 active; M5 inactive)

Half-life elimination:

• Ivacaftor: 13.7 ± 6.06 hours
• Tezacaftor: 15 ± 3.44 hours

Time to peak:

• Ivacaftor: Median: approximately 6 hours (range: 3 to 10 hours)
• Tezacaftor: Median: approximately 4 hours (range: 2 to 6 hours)

Excretion:

• Ivacaftor: Feces (87.8%); urine (6.6%)
• Tezacaftor:
  • Feces (72% as unchanged drug or in form of M2 metabolite);
  • urine (14% [in form of M2 metabolite],
  • <1% of administered dose as unchanged drug)

International Brands of Tezacaftor and ivacaftor:

• Symdeko
• Symkevi

Tezacaftor and ivacaftor Brands Names in Pakistan:

No Brands Available in Pakistan.