Enzyme inducers and oral contraceptive pill

• hepatic enzyme-inducing anti-epileptic drugs (AEDs) increase the metabolism of both progesterone and oestrogen. As the concentrations of these hormones may be lowered by 50% or more, adjustments are required in contraceptive regimes to ensure that pregnancy is prevented
• NICE state (1):
  • if a woman or girl taking enzyme-inducing AEDs chooses to take the combined oral contraceptive pill, guidance about dosage should be sought from the SPC and current edition of the BNF
    
    
  • the progestogen-only pill is not recommended as reliable contraception in women and girls taking enzyme-inducing AEDs
    
    
  • the progestogen implant is not recommended in women and girls taking enzyme-inducing AEDs
    
    
  • the use of additional barrier methods should be discussed with women and girls taking enzyme-inducing AEDs and oral contraception or having depot injections of progestogen
    
    
  • if emergency contraception is required for women and girls taking enzymeinducing AEDs, the type and dose of emergency contraception should be in line with the SPC and current edition of the BNF
    
    
  • discuss with women and girls who are taking lamotrigine that the simultaneous use of any oestrogen-based contraceptive can result in a significant reduction of lamotrigine levels and lead to loss of seizure control. When a woman or girl starts or stops taking these contraceptives, the dose of lamotrigine may need to be adjusted

A comprehensive guidance regarging oral contraception and the use of enzyme inducing drugs has been produced (2):

• enzyme inducing drugs that may decrease contraceptive efficacy:
  • antiepileptics (e.g. carbamazepine, eslicarbazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, topiramate)
    
    
  • antibacterials (e.g. rifabutin, rifampicin)
    
    
  • antiretrovirals (e.g. efavirenz, nevirapine). Ritonavir reduces the bioavailability of estrogen and may reduce the bioavailability of progestogens by inducing glucuronidation
    
    
  • antidepressants (e.g. St John's wort - a herbal preparation)
    
    
  • others (e.g. modafinil, bosentan, aprepitant, lumacaftor)
    
• Use of contraceptive methods when woman is using an enzyme-inducer (and within 28 days of stopping treatment)
  
  
  • women starting enzyme-inducing drugs should be advised of potential interaction with hormonal contraception and be offered a reliable method unaffected by enzyme-inducers
    
    
  • women using enzyme-inducing drugs who require emergency contraception (EC) should be advised of the potential interactions with oral methods and offered a Cu-IUD. If a Cu-IUD is unacceptable or unsuitable, a double dose of levonorgestrelcontaining emergency contraception (LNG-EC) may be used
    
    
  • short-term use of enzyme-inducing drugs (<2 months) can be managed more flexibly than longer-term use. Continuing the method with consistent and careful use of condoms may be appropriate
    
    
  • combined hormonal contraceptive (CHC) (2)
    • not advised - recommend an alternative method
      
      
    • women taking rifampicin and rifabutin should always be advised to change to an alternative method. If a woman wishes choice with other enzyme-inducing drugs, consider use of a minimum 50 µg(30 µg plus 20 µg) ethinylestradiol (EE) monophasic pill during treatment and for a further 28 days with a continuous or tricycling regimen plus pill-free interval of 4 days
      • this method is suitable for women taking enzyme-inducing medicines (except the teratogen topiramate) for any given duration (7)
        • the total combined ethinylestradiol from the two monophasic pills must be at least 50 micrograms per day. An example of a regimen is: using two monophasic COC pills each containing 30 micrograms ethinylestradiol (total 60 micrograms ethinylestradiol).
          
          
    • breakthrough bleeding may indicate low serum EE concentrations. Exclude other causes (e.g. chlamydia) and dose of EE can exceptionally be increased up to a maximum of 70 µg EE after specialist advice
      
      
    • use of two patches or two rings is not recommended
      
      
  • progestogen-only pill (POP)
    • not advised - recommend an alternative method
      
      
  • progestogen-only implant
    • not advised - recommend an alternative method
      
      
  • DMPA, progestogen-only injectable: depot medroxyprogesterone acetate
    • no interaction -no need for extra precautions
      
      
  • levonorgestrelcontaining intrauterine system (LNG-IUS)
    • no interaction -no need for extra precautions
      
      
  • copper-bearing intrauterine devices (Cu-IUDs)
    • no interaction -no need for extra precaution

A MHRA review re: antiepileptic drugs in pregnancy states (6):

Summary of key conclusions of review

• Lamotrigine – Studies involving more than 12,000 pregnancies exposed to lamotrigine monotherapy consistently show that lamotrigine at maintenance doses is not associated with an increased risk of major congenital malformations

• Levetiracetam – Studies involving more than 1,800 pregnancies exposed to levetiracetam do not suggest an increased risk of major congenital malformations

• For both lamotrigine and levetiracetam, the data on neurodevelopmental outcomes are more limited than those for congenital malformations. The available studies do not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to either lamotrigine or levetiracetam; however, the data is inadequate to rule out definitively the possibility of an increased risk

• For the other key antiepileptic drugs, data show:
  • an increased risk of major congenital malformations associated with carbamazepine, phenobarbital, phenytoin, and topiramate use during pregnancy
  • the possibility of adverse effects on neurodevelopment of children exposed in utero to phenobarbital and phenytoin
  • an increased risk of fetal growth restriction associated with phenobarbital, topiramate, and zonisamide use during pregnancy

Actions for prescribers

• At initiation and as part of the recommended annual review for patients with epilepsy, specialists should discuss with women the risks associated with antiepileptic drugs and with untreated epilepsy during pregnancy and review their treatment according to their clinical condition and circumstances – we have produced a safety information leaflet to assist with this discussion

• Urgently refer women who are planning to become pregnant for specialist advice on their antiepileptic treatment

• All women using antiepileptic drugs who are planning to become pregnant should be offered 5mg per day of folic acid before any possibility of pregnancy

• For lamotrigine, levetiracetam or any antiepileptic drugs that can be used during pregnancy, it is recommended to
  • use monotherapy whenever possible
  • use the lowest effective dose (see below for key dose monitoring advice, including for lamotrigine and levetiracetam)
  • report any suspected adverse effects experienced by the mother or baby to the Yellow Card scheme

Reminder of advice to give to women with epilepsy

• Do not stop taking antiepileptic drugs without discussing it with your doctor

• If you are taking an antiepileptic drug and think you may be pregnant, seek urgent medical advice, including urgent referral to your specialist

• Read the patient information leaflets that accompany your medicines and other information provided by your healthcare professional

Notes:

• Metabolism - enzyme induction
  • Cytochrome P-450 is the most important family of enzymes in drug metabolism
    • If cytochrome P-450 enzymes are induced, the metabolism of concomitant drugs may be increased, potentially reducing the clinical effect. Once started, these drugs may induce cytochrome P-450 enzymes within 2 days and the effects are generally maximal within 1 week. After cessation, enzymes generally return to their previous level of activity within 4 weeks
    • If cytochrome P-450 enzymes are inhibited, the metabolism of concomitant drugs may be decreased, potentially leading to toxicity and increased side effects
      
      
• enzyme inducers and the combined pill
  • enzyme activity does not return to normal for several weeks after stopping an enzyme-inducing drug - therefore appropriate contraceptive measures are required for 4 weeks for the liver enzymes to return to normal functionality (2)
    • therefore higher doses of the COC, with or without additional contraceptive protection, should be continued for 4 weeks after stopping the AED (4)
      • this period should be increased to 8 weeks after more prolonged used of enzyme inducers. In all cases, the PFI should be omitted when switching back to a standard or low-dose COC (4)
        
        
• other (2)
  • lamotrigine (antiepileptic) and griseofulvin (antifungal) are not thought to be enzyme-inducing drugs; however, contraceptive efficacy may be reduced by concurrent use. The clinical significance of this effect is unknown
    • women taking lamotrigine should be advised that CHC may interact with lamotrigine; this could result in reduced seizure control or lamotrigine toxicity. The risks of using CHC could outweigh the benefits (5)
  • progestogen receptor modulators:
    • recent evidence suggests that quick starting hormonal contraception after ulipristal acetate (UPA) for emergency contraception (EC) may reduce EC effectiveness. There is also a theoretical risk that ulipristal acetate (e.g. EllaOne for EC or Esmya for treatment of fibroids) may reduce efficacy of hormonal contraception, although this has not been demonstrated to date in clinical studies
    • Women should be advised to wait 5 days after taking ulipristal acetate for emergency contraception (UPA-EC) before starting CHC. Women should be made aware that they must use condoms reliably or abstain from sex during the 5 days waiting and then until their contraceptive method is effective (5)
      

Reference:

1. NICE (April 2018). Epilepsies: diagnosis and management
2. Faculty of Sexual & Reproductive Healthcare Clinical Guidance.Clinical Guidance: Drug Interactions with Hormonal Contraception January 2018.
3. BNF 7.3.1
4. NHS Specialist Pharmacy Service (May 2019). Which combined oral contraceptive pill is suitable in a patient who is taking hepatic enzyme-inducing drugs, such as carbamazepine, phenytoin, rifampicin or rifabutin?
5. FSRH (July 2019). Combined Hormonal Contraception
6. MHRA(January 2021).Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review Drug Safety Update volume 14, issue 6: January 2021: 1
7. NHS Specialist Pharmacy Service (February 2023). Using contraception with enzyme-inducing medicines