A very brief overview of SmPC safety sections 4.5 Drug Interaction 4.6 Fertility, pregnancy and lactation 4.7 Driving- things to know

 Safety sections of SmPC (or RSI) include Section 4.5 Interaction with other medicinal products and other forms of interaction, section 4.6 Fertility, pregnancy and lactation and section 4.7 Effects on ability to drive and use machines (or analogues sections). In this article, I have attempted to discuss salient points relevant to these sections in brief based on EMA guidelines and ICH.

As you go through this article, you can refer to some SmPCs as examples.

Links are added below:

1-     Atorvastatin SmPC:

2-     Acetylsalicylic acid SmPC:

Now let’s go section by section for each of them and discuss the key points which matter.

 Section 4.5 Drug interactions/ Interaction with other medicinal products and other forms of interaction

• This section should provide information on the potential for clinically relevant interactions based on the pharmacodynamics properties and in vivo pharmacokinetic studies of the medicinal product
• Information should highlight clinically relevant interactions, i.e. those resulting in recommendation on the use of this medicine or other medicines

Depending on the safety profile of drug, recommendations in 4.5 may be:

• Contraindications of concomitant use
• Concomitant use not recommended
• Precautions including dose adjustment mentioning situations where these may be required e.g. duration of clinically important interaction considering discontinuation (e.g. enzyme inhibitor or reducer) or need for washout period
• Any clinical manifestations and effects on plasma levels and AUC of parent compounds or active metabolites and/or on laboratory parameters should be given
• Mechanism of the interaction should be explained if known
• Interactions affecting the use of the medicinal product should be given first, followed by those interactions resulting in clinically relevant changes on the use of others
• Cross reference to section 4.2, 4.3, 4.4, and/or 5.2 as appropriate

·      Information on other relevant interactions such as with herbal medicinal products, food, alcohol, smoking, or pharmacologically active substances not used for medical purpose, should also be given.

·      With regard to pharmacodynamics effects where there is a possibility of a clinically relevant potentiation or a harmful additive effect, this should be stated

Other important points to consider for section 4.5:

·      If no interaction studies have been performed, this should be clearly stated

·      In vitro data should be summarized in section 5.2 and not in section 4.5 unless the data results in a change in the use of the medicinal product

Use a separate subheading for:

• Other special populations
• Paediatric population

Common formula for 4.5

• Any clinical manifestations, effects on plasma levels + AUC of parent compounds, active metabolites +/-laboratory parameters
• Mechanism of the interaction

 Special population:

PATIENT GROUPS to be considered for 4.5 in which:

• The IMPACT OF AN INTERACTION IS MORE SEVERE,
• THE MAGNITUDE OF AN INTERACTION IS EXPECTED TO BE LARGER

 e.g., patients with decreased renal function (in case the parallel pathway is renal excretion), paediatric patients, elderly etc, this information should be given here

Any identified treatment recommendations should be given in relation to concomitant use in paediatric subset(s) such as:

• Dose adjustment
• Extra-monitoring of clinical effect marker/adverse reactions
• Therapeutic drug monitoring

 Section 4.6 Fertility, pregnancy and lactation

General objectives of section 4.6 Fertility, pregnancy and lactation:

Information on the use of a medicine in relation to reproduction refers to a number of aspects:

• Fertility
• Pregnancy
• Breastfeeding
• Health of the fetus
• child and mother

Special points to consider for section 4.6 Pregnancy

All available knowledge from pharmacological data, non-clinical studies, clinical data and therapeutic practice should be taken into account:

• Practical recommendations should be made, providing reasons for such recommendations to facilitate healthcare professionals’ information to the patient
• Efforts should be made to update the recommendations on the basis of human experience in exposed pregnancies which may supersede initial non-clinical data
• If appropriate, cross reference should be added to section 4.3 (in case of contraindication), 4.4 (e.g. when contraceptives measures are required), 4.5 (if interaction with contraceptives), 4.8 or 5.1 (details of clinical data), or, 5.3 (details of non clinical data)
• Section 4.6 should therefore be reviewed with due consideration to the CHMP Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling and the standard statements included in its Appendix 3

Some more points relevant to pregnancy section of 4.6

• Conclusions of non-clinical reproductive toxicity (details to be provided in Section 5.3)
• Comprehensive information on human data/Extent of the human experience
• Recommendations on the use in women of childbearing potential and on contraceptive measures (in males and females), when appropriate
• Recommendations on the use of the medicine during different periods of gestation
• Recommendations on the management of exposure during pregnancy when appropriate, including relevant specific fetal or neonatal monitoring

Use in lactation:

Clinical data:

• Conclusions of kinetic studies (e.g. transfer into milk)
• If available, information on adverse reactions in nursing neonates

Only if there is no human data, conclusions from non-clinical studies on the transfer into milk

Recommendations should be given:

• To stop or continue breastfeeding
• To stop or continue the treatment

Fertility

• The main information on the possible effects of the medicinal product on fertility (male and female) must be included in section 4.6
• Clinical data and relevant conclusions from non-clinical toxicity studies, if available
• Recommendation for use of the medicinal product when pregnancy is planned but fertility might be affected by treatment should be included
• If there are no fertility data at all, this should be stated

Section 4.7: Effects on the ability to drive and use machines

General objectives of section 4.7 Effects on the ability to drive and use machines

This section should provide information regarding the influence of the medicinal product on the ability to drive and use machine based on:

• The pharmacodynamics and pharmacokinetic profile
• Reported adverse reactions or specific studies in a relevant target population addressing the performance related to driving and road safety or using machines

Points to consider:

Various wordings to be used for this section depending on the profile of drug:

• No or negligible influence on these abilities
• Minor influence (elaborate)
• Moderate influence (elaborate) + special warnings/precautions for use
• Major influence (elaborate) + special warnings/precautions for use + also mention in section 4.4

Other important factors that affect the ability to drive and use machines should be considered if known, such as

• Duration of the impairing effect
• The development of tolerance or adverse reactions with continued use

 Many thanks for reading this brief article, I hope you liked it and I look forward to conversation in comments or msgs :-)

Further readings: