Frontline Combo is essentially the same as the Spot-on, but Combo has an additional ingredient. This lasts for longer on the coat, so has an effect if there is an extended delay in re-applying the frontline. The extra ingredient is probably just as safe as the main ingredient, the prescription status might well be a commercial decision by the manufacturer.
The extra ingredient does not kill fleas, but in fact stops them from breeding. Since an individual flea does not live for long, stopping them breeding is an effective way of preventing fleas build up in the environment.
Most people consider that there is little effective difference between the 2 products, but if you try to extend the periods between successive applications, Combo is slightly better. Safety of them both is very high and probably not a significant concern