Women on certain TB, HIV and epilepsy drugs using the contraceptive device Implanon NXT risk falling pregnant as these drugs render the device less effective.
According to a Health Department internal circular issued in October, "new evidence has emerged that certain enzyme-inducing drugs" such as the TB drug Rifampicin, antiretroviral drug Efavirenz and epilepsy drugs, Carbamazepine, Phenytoin and Phenobarbital "interfere with action and effectiveness" of Implanon.
More than 500,000 women use the new contraceptive, the size of a matchstick, implanted in the upper arm, which was introduced last year.
The circular - issued by Dr Yogan Pillay, the department's deputy director-general: HIV/Aids, TB and Maternal, Child and Women's Health - advises healthcare staff against prescribing Implanon to women on these drugs.
It advises that women on these drugs and already fitted with Implanon be given an option to remove the device.
The circular comes almost a year after Health Minister Aaron Motsoaledi rolled out Implanon NXT to the public free of charge.
Hailed as the most effective contraceptive and effective for up to three years, Implanon releases progesterone - a hormone that prevents pregnancy.
The circular recommends that women on Rifampicin and already implanted with Implanon "should be covered with another non-hormonal contraceptive method [intrauterine devices or condoms] for the duration of their TB treatment".
Over 2.7million people in South Africa are on ARVs, with 1.5million on a fixed-dose combination.
The fixed-dose combination contains Efavirenz.
However, Dr Sindi van Zyl, an HIV/Aids specialist at Anova Health Institute, said "not all regimens contain Efavirenz. Some contain Aluvia."
Health Department spokesman Joe Maila said it was watching for any adverse effects and contra-indications.
About 521 896 women are using Implanon.
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