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The mechanism of action of modafinil is different from that of amphetamine and ephedrine or other similar psychostimulants. Modafinil is also not formed in the human body from amphetamine or ephedrine derivatives.

Modafinil affects different areas of the brain. Probably the most important effect is the increased speed of mental reactions. This effect refers to the lower part of the diencephalon, the hypothalamus, where the activation of neural pathways occurs, in which the action of orexin/hypocretins is realized, which play an important role in the regulation of sleep-wakefulness as intermediary substances.

In addition, it activates the sympathetic alpha-1 receptors of the central nervous system, increases the activity of stimulation of glutamine and histamine transmitters, and also enhances the effects of serotonin in the cerebral cortex.

In addition, it reduces the activity of those inhibitory nerve cells in which gamma-aminobutyric acid acts as a transmitter. However, the exact mechanism by which modafinil promotes wakefulness is unknown.

Unlike amphetamine, modafinil does not stimulate the dopamine system of the central nervous system.

Course with Modafinil for women

Advice for healthcare professionals

  • modafinil potentially increases the risk of congenital malformations (including congenital heart defects, hypospadias, and orofacial clefts); modafinil should not be used in pregnancy and alternative treatment options for narcolepsy should be considered
  • women of childbearing potential must use effective contraception during treatment and for 2 months after stopping modafinil
  • modafinil may reduce the effectiveness of steroidal contraceptives, including oral contraceptives, therefore alternative or concomitant methods of contraception are required
  • ensure all female patients of childbearing potential taking modafinil are informed and fully understand that:
  • modafinil should not be used during pregnancy due to the increased risk to the fetus
  • effective contraception is needed during treatment with modafinil and for 2 months after stopping modafinil treatment
  • they should discuss plans for pregnancy early with their doctor and continue contraception for 2 months after stopping modafinil
  • report any suspected adverse reactions experienced by a woman or child associated with medicines taken during pregnancy.
Advice for healthcare professionals

Review of safety in pregnancy

Modafinil (Provigil, generics) is indicated in adults for the treatment of excessive sleepiness associated with narcolepsy with or without cataplexy (see full indication in summary of product characteristics). Narcolepsy is a rare long-term brain condition that causes excessive daytime sleepiness, cataplexy (loss of muscle tone), and sleep disturbance. Recommended supportive measures for narcolepsy symptoms include behaviour modifying measures, sleep hygiene, and scheduled daytime naps.

A European review concluded that there was a possible increased risk of congenital malformations in the children of women treated with modafinil during pregnancy. The product information, including the patient information leaflet, has been updated and a letter sent to prescribers of modafinil in January 2020.

The review considered data from a prospective US registry and spontaneous reports of major congenital malformations including congenital heart defects, hypospadias, and orofacial clefts, for which causal relationship with modafinil was considered possible. The MHRA has considered the European review and other safety data, which support the suggestion of an increased risk of major congenital malformations with use of modafinil in pregnancy.

The available data, although limited and conflicting, provide evidence that modafinil/armodafinil use in pregnancy may increase the risk of congenital malformation. Of the three largest studies currently available (each describing <100 first trimester-exposed pregnancies), two identified increased risks, with the controlled study indicating an approximate 3-fold increased risk attributable to modafinil exposure.

The remaining study found no increase in the rate of malformation following first trimester modafinil exposure. Due to the limited and conflicting nature of the available evidence, it is currently unclear if first trimester modafinil exposure truly increases the risk of fetal malformation.

If the evidence indicating an increased risk of malformation is accurate, the data suggest that approximately 4 to 6 additional malformed infants could be expected for every 100 modafinil-exposed pregnancies (relative to an expected background rate of 2 to 3 per 100). A single uncontrolled study described a rate of miscarriage consistent with the expected background rate following maternal modafinil/armodafinil use in early pregnancy. However, the available data are provided by a single uncontrolled case series and therefore additional studies are required.

No studies have investigated the risk of stillbirth, preterm delivery, growth restriction, neurodevelopmental impairment or neonatal complications following modafinil use in pregnancy. Although the risk of neonatal withdrawal has not been formally studied, as modafinil is a centrally acting medication, symptoms of withdrawal may be experienced following its use in the latter stages of pregnancy.
It is important to ensure that the maternal condition for which modafinil is prescribed is appropriately treated during pregnancy. It is strongly recommended that the potential risks and benefits of continued use, as well as any potential alternatives, are discussed with UKTIS.

Review of safety in pregnancy
Modafinil
Course with Modafinil for men