Pharmaceutical companies in India employ armies of medical representatives to pitch a drug to doctors.
“We promoted it for typhoid and urinary tract infection mainly,” Jessy Prashanth, a former rep for Abbott in the state of Andhra Pradesh, said of Zimnic AZ. “But we also asked doctors to use it in cases of persistent cough, cold and fever.” Prashanth now works for Alkem Laboratories Ltd, an Indian company that sells the same combination under a different brand name.
A medical representative working for Abbott in Maharashtra state, who spoke on condition of anonymity, said he only promoted the drug for respiratory tract infections and typhoid. But from visits to chemists and doctors, he was aware it was being prescribed for “everything from soft skin tissue infections, pneumonia, respiratory tract infection, to (urinary tract infection), severe fever, typhoid fever and sexually transmitted diseases,” he said. “It covers most things people go to a general practitioner for.”
The two antibiotics that make up Zimnic AZ attack similar bugs in the body and have the same potential side effects, said Jonathan Zenilman, chief of the infectious diseases division at Johns Hopkins Bayview Medical Center in Baltimore. By coupling cefixime and azithromycin in one dose, he said, patients face a heightened risk of gastrointestinal side effects, like nausea, vomiting and diarrhea.
“It doesn’t make sense,” he said. “The toxicity is duplicative.”
Akums, the manufacturer of Zimnic AZ, said no adverse drug reactions have been reported since the combination has been on the market. For four years after a new medication is approved by the central government in India, drugmakers are required to submit a Periodic Safety Update Report to New Delhi, which should include adverse reactions.
Akums said Abbott regularly submitted update reports for Zimnic AZ. Neither Akums nor Abbott responded to requests to see the findings.
India’s system for collecting data on problematic drug reactions is weak. The country reported about 37,800 suspected cases of adverse drug reactions to the World Health Organization’s global database last year. China, with a comparable population, submitted close to 214,000 reports for the same period, while the United States reported some 785,000 cases.
Drug-resistant typhoid
Standing in his chemist shop in the Uttarakhand capital of Dehradun, pharmacist Varat Negi said he usually fills Zimnic AZ prescriptions for throat infections and tonsillitis.
“Many doctors prescribe it,” Negi said, pointing reassuringly to the Abbott logo on the back of the blister pack. “It’s a big company.”
Cefixime and azithromycin have been administered together before - but usually as two separate drugs, and to treat very specific problems. The US Centers for Disease Control and Prevention (CDC) says the two drugs may be used together as an alternative treatment for gonorrhea, a sexually transmitted disease.
Results from a study sponsored by the Center of Geographic Medicine and Tropical Disease at the Sheba Medical Center in Israel also suggest a combined therapy of the two drugs was effective in treating drug-resistant typhoid, said Eli Schwartz, the doctor who conducted the research. Israeli doctors started to look into the treatment because travelers were bringing drug-resistant typhoid back to Israel from India and Nepal, he said.
Still, growing drug resistance is a key risk of the widespread misuse of antibiotic fixed-dose combinations, especially in a country like India where prescription drugs are frequently sold over the counter. Bacteria develop resistance to antibiotics when repeatedly exposed to the same drugs over time.
The Central Drugs Standard Control Organization (CDSCO), the regulatory office headed by the drug controller, has tried several times to tame the fixed-dose combination market in the past decade. In 2007, the government ordered states to withdraw 294 combinations that were on the market without the approval of the central government.
It didn’t go well. In southern India, drug companies and industry associations took the government to court over the order. The court stayed the withdrawal order, and eight years on, the cases are still pending in the Madras High Court.
Now the drug controller is trying again. In a review of some 6,200 drugs completed earlier this year, only about 40% were considered ready for approval by a government-appointed committee. Some 15% to 20% were deemed “irrational,” according to the drug regulatory official who spoke on condition of anonymity.
The government has yet to demand that the irrational drugs be removed from the market. Instead, it has issued the equivalent of a show-cause notice to drugmakers, giving them another opportunity to justify these products.
Drugs Controller General Singh said his office is committed to ensuring patient safety and that he was confident states were no longer granting manufacturing licenses for new drugs. But he said the government was giving drugmakers another chance to make a case for their products.
Akums, the drugmaker that manufactures Zimnic AZ for Abbott, received a government notice in September saying Akums needed to provide regulators with more information, said former company chairman Jain. Otherwise, the combination of cefixime and azithromycin would be considered irrational. Akums provided additional data to the government, and in late November the combination was still under review, Jain said.
Abbott declined to say whether it was informed of the notice sent to Akums.
For Prabhu Dayal, the patient with a cold and cough, Zimnic AZ wasn’t a quick fix. Contacted two weeks after he was prescribed the drug, Dayal said he had completed the course but still wasn’t feeling well.
So, he went to get another round of Zimnic AZ from the chemist, he said. It was sold to him again - this time without a new prescription.
