A mix of epilepsy medications that interact unpredictably. A flawed cough syrup axed by U.S. regulators more than 3 decades ago. An untested antibiotic cocktail with a high potential to breed drug resistance.
You can't buy any of these drugs in the U.S. But until just a few months ago, American pharmaceutical companies were selling all of them in India. They are among dozens of unproven and often risky drug cocktails that Western drugmakers have been marketing there for years -- and in many cases still are -- even though they are not approved in their home countries.
Increasingly, this double standard has health activists and researchers crying foul.
"Why would you sell something to Indian patients that you're not permitted to sell to American ones?" says Patricia McGettigan of Barts and The London School of Medicine and Dentistry in the U.K., who recently published a. "For a multinational company to know that its product would not be approved or was actually removed from the market in its own country, to then go and sell that in India is both cynical and wrong."
The criticism comes on the heels of a March notification from India's Ministry of Health that outlawed 344 questionable drug combos, threatening to eat away of the drug market. If more combinations are added, the pharmaceutical industry may lose as much as .
While health activists hailed the ban as "remarkable," local firms and the Indian units of multinational giants such as U.S.-based Abbott Laboratories and Pfizer are currently fighting it in court. They have been granted a temporary stay for certain products during the hearings.
Hundreds of Names for One Drug
Chinu Srinivasan from All India Drug Action Network, an independent group advocating rational use of medicines, feels global companies in particular should know better than to sell these drugs in India.
"What they will not do in their own country, they do it here," says Srinivasan, who called the ban "one of the greatest interventions" for public health since India's independence from the British in 1947. His group, along with the he helps to run, has joined the court case in support of the government.
To an outsider, India's drug market may seem almost as complicated and chaotic as the country itself. With thousands of competing manufacturers, historically permissive patent rules and weak regulation, the number of products is in the tens of thousands; sometimes the same active ingredient is sold under hundreds of different brand names, or the same name may be used for different drugs.
Many of the medicines are mixtures of individual drugs, so-called fixed-dose combinations. These are used globally to reduce patients' pill burden, but in India they have exploded. According to Srinivasan and other industry insiders, adding more ingredients to a product means companies can claim more benefits and reach more patients.
Today, nearly half the drugs sold in India are fixed-dose combinations, compared to less than 14% in the U.S. More than a thousand such products , and lax enforcement has allowed manufacturers to market of additional combinations based solely on manufacturing licenses from individual states. Many exist nowhere else in the world and their safety and efficacy are largely unknown.
As a government-appointed panel of Indian doctors and public health experts , "The market is flooded by irrational, nonessential, and even hazardous drugs that waste resources and compromise health."
Research shows that health providers, in turn, are quick to prescribe inappropriate medicines, due in part to incentives from drugmakers and a lack of competence.
To gain a stronger foothold in India's crowded market, multinational drugmakers have acquired many of these dubious products from local companies, says Chandra Gulhati, the Delhi-based editor of MIMS, a commercial drug compendium.
"They went into this cutthroat competition with Indian companies, which they couldn't sustain. So they just bought left and right these irrational combinations, because it increased their sales," he says. "They know very well that such combinations will never be approved in Western countries."
"Poor and Risky Combination"
Take , a mix of the antibiotics cefixime and azithromycin. Very rarely are both drugs needed together, and so patients will be taking at least one of them unnecessarily, risking side effects without any chance of benefiting. What's more, because antibiotics breed resistant "superbugs" that spread globally, using the medicines casually makes them less effective for people who really need them.
Sold by Abbott in India, Zimnic AZ has not been approved for sale in major markets such as the U.S. and U.K., a from December found.
, another Abbott product, blends a couple of old epilepsy drugs -- phenytoin and phenobarbital -- that are in an unpredictable way. One of the components, phenobarbital, is highly sedative. The result is "a very poor and risky combination," according to McGettigan.
Both Zimnic AZ and Garoin are among the newly banned combinations. However, Abbott has been granted a temporary injunction of the prohibition of Garoin, which the firm says was introduced prior to 1988 legislation requiring pre-manufacturing central approval before state manufacturing licenses are granted.
Like other drug companies contacted for this story, Chicago-based Abbott did not answer questions about why it sells products in India that are not marketed in developed countries. A spokesman said in an email that Garoin, which has not been approved in major markets such as the U.S., Canada or the U.K., was "designed to improve patient adherence."
"Garoin has been in use for over three decades and is an important option in the treatment of epilepsy," he added.
Mixing drugs in a single pill may help boost compliance when patients need several medicines at the same time, as in HIV or tuberculosis. But most often the downsides outweigh the benefits, according to James McCormack, a professor of pharmaceutical sciences at the University of British Columbia in Vancouver.
Even if the individual ingredients are compatible, combining them means you can't figure out which one is working and which one is causing side effects. And you can't adjust the dose of one without affecting the other, too.
"It flies in the face of how you're supposed to properly use medications," says McCormack.
Abbott acquired Garoin and Zimnic AZ when it bought the branded-generics business of Mumbai-based Piramal Healthcare in 2010. Neither drug has marketing approval from India's central drug regulator. Instead, they have been sold based on state manufacturing licenses, which have been granted for years without proof of efficacy and safety.
Approved in India, Banned Elsewhere
According to Gulhati at MIMS, the new ban represents only "the tip of the iceberg," with hundreds of dubious combinations still on the market. Some are authorized for sale, but that doesn't necessarily mean much, he says.
For example, Johnson & Johnson got approval in India in 2008 for a cough syrup called Clistin. Twenty-six years earlier, the U.S. Food and Drug Administration pulled J&J's Clistin Expectorant, a near-identical product, from the market after it found it each other. Later, one of the key ingredients, carbinoxamine, was linked to 21 baby deaths.
The New Brunswick-based company declined to address the FDA's concerns and did not say whether it had submitted safety and efficacy data to India's drug regulator prior to approval. In an email, a spokeswoman said Clistin was divested to an Indian firm in February. She also noted that it was not approved for children under 2 and was prescription-only.
However, "There is no difference between prescription and OTC in India," says Gulhati. "You can get anything OTC."
For cough syrups, such as Pfizer's Corex and Abbott's Phensedyl that are also combination products and contain the addictive narcotic codeine -- Clistin does not -- the problem is particularly acute, as Gulhati points out.
Near his home in south Delhi, two pharmacies lie next to a group of restaurants that stay open until midnight. "If you go at 6 o'clock in the morning to those chemist shops," Gulhati says, "you will find scores of empty bottles of Corex and Phensedyl lying on the road. Addicts have bought them, consumed them and thrown them away."
The two products are among the 10 bestselling brands on India's drug market. According to data from PharmaTrac, a commercial database, more than 48 million bottles of Corex and 33 million bottles of Phensedyl were sold in India last year, grossing some $84 million.
When India's government outlawed these popular syrups and others like them in March, it noted they were risky and that safer alternatives exist. Codeine-based products are available worldwide, but regulators in the U.S., Canada and Europe all warn that they shouldn't be used to treat cough and cold in children.
New York-based Pfizer, which along with Abbott has been granted a stay on the ban of its codeine-based cough syrup, said in an email that "Corex has a well-established efficacy and safety profile in India for more than 30 years and has both Central and State licenses and approvals." The company declined to answer further questions citing the ongoing court case.
Dhirendra Singh, a Delhi-based lawyer who is crusading against the drugs and has impleaded himself in the case, says addiction to Corex and Phensedyl is costing lives. In the town where he grew up, he knows "at least a dozen families" that have lost someone to codeine-based cough syrups.
"I've seen with my own eyes youngsters dying, kids I knew growing up," says Singh, who feels companies from developed countries are exploiting India's weak enforcement to make a profit.
"The system can't cope," he says. "Who's caught in between? Families and youngsters."