The overhaul is part of a major realignment in the global pharmaceuticals industry as it strives to cope with a clampdown in health spending by cash-strapped governments.
"The transactions mark a transformative process for us," said Novartis Chief Executive Joe Jimenez, who has been undertaking a strategic review of the once-sprawling business.
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Novartis said it had agreed to buy GlaxoSmithKline's oncology products for $14.5 billion, while selling to GSK its vaccines, excluding flu, for $7.1 billion plus royalties and creating a joint venture with GSK in consumer healthcare.
Novartis also said it had agreed to sell its animal health arm to Eli Lilly for approximately $5.4 billion.
The global pharmaceuticals sector has seen a flurry of deal-making recently as large companies seek to focus on a small number of leading businesses, while smaller speciality and generic producers seek greater scale.
Cancer is a particular focus for some drugmakers, thanks to novel medicines that show promise by boosting the body's immune system. Tuesday's deal will see Novartis strengthen its world No.2 position in cancer behind cross-town rival Roche.
A desire to boost its oncology business is seen as a key factor behind Pfizer's reported interest in AstraZeneca. A weekend newspaper said Pfizer, which has also been spinning off assets such as animal health and baby food, had made a 60 billion pound ($101 billion) bid approach that had been rebuffed by the British firm.
"We reckon the real value of the deal should be searched for in the pipeline and the newly launched products, strengthening Novartis' position in melanoma and haematology," Vontobel analyst Andrew Weiss said of the cancer deal with GSK.
Cancer is an extremely competitive marketplace, however, and some analysts said it made sense for GSK to exit a field where it was only No.14 in the world.
As well as strengthening its vaccines business, GSK will take the lead in running a future consumer health business worth about $10 billion in annual revenue with Novartis. The British drugmaker will return 4 billion pounds to shareholders as well.
At 0905 GMT, Novartis shares were up 2.3% to 76.4 Swiss francs. GSK shares were up 5.4% to 1,643.5 pence.
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Novartis's Jimenez told reporters the deals would result in slightly lower overall sales for the Swiss group, but higher profit as it swaps lower-margin vaccines business for higher-margin oncology drugs.
Analysts at Swiss broker Notenstein said the new cancer drugs would help Novartis to navigate patent expiries on top-selling medicines more easily.
However, analysts at Barclays described the price tag for the oncology assets, which could rise as high as $16 billion if certain milestones are reached, as "rather hefty."
Novartis said it would start a separate sale process for its flu business immediately, which was not part of the GSK deal.
Eli Lilly will have the world's No.2 animal health business by revenue in the wake of its deal with Novartis. It said it would fund the transaction with $3.4 billion of cash and $2 billion of loans and expected cost savings of about $200 million per year within three years of closing the deal.
BofA Merrill Lynch advised Lilly, while Goldman Sachs Group Inc advised Novartis on the animal health deal. GSK said Lazard and Zaoui & Co. were acting as its joint financial advisers.
($1 = 0.5951 British Pounds)
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