On my 180nm process, the checking window for density is 1x1 mm. If you make a smaller asic (4mm sqr), it is possible to make this very un-uniform, since the asic is only 4 times the window.
Are extra precautions needed? (like forcing a smaller density window)
You don't need to fill them with "active" metal, you can usually
1) fill with metal and ground it --- make sure to not add extra capacitance to your active signals
2) let the foundry auto-fill -- they usually know what they are doing, but you should read the manual to make sure it fits your needs..... you don't want the foundry to fill in the middle of a sensitive circuit