Takeda Pharmaceutical shareholders have approved the company's $59 billion takeover of London-listed Shire.
The deal will create a global powerhouse with a stronger drugs pipeline but one that is saddled with massive debt.
Almost 90% of Takeda shareholders voted to approve the deal at an extraordinary general meeting held in Osaka, the company said.
Takeda will be joining the ranks of the world's top 10 drugmakers and gaining expertise in rare diseases through the deal, the biggest overseas acquisition by a Japanese company.
It will also become one of the most indebted. In addition to issuing new shares, the company has secured $30.9 billion in bank loans.
Takeda shares have fallen around 25% since the drugmaker revealed its interest in the acquisition in March, with investors worried about whether the company can cope with high financing costs and challenges of integration.
While today's approval was expected, a small group of investors had actively voiced opposition.
"We are definitely against this because the financial risks are too great and the expected benefits are quite limited," said Kazuhisa Takeda, a former director of the drugmaker and a member of the founding family, ahead of the meeting.
"I think M&A is quite necessary for Takeda's future but Shire is not the answer," he added.
Chief executive Christophe Weber has promised to turn the deal profitable by slashing costs.
It predicts annual savings of at least $1.4 billion three years after completion, and expects to boost underlying earnings significantly from the first full year after closing.
Takeda also has a plan to sell up to $10 billion worth of non-core assets to pay back debt.
Analysts have said it may be difficult to integrate the two companies.
Toshiba's acquisition of Westinghouse over a decade ago and Japan Post Holdings' $4.9 billion bet on Toll Holdings are widely seen as examples of many Japanese companies having paid high valuations in cross-border deals only to face massive write-downs later.
But they also said Takeda has little choice but to seek growth abroad, with industry pressure to gain access to cutting-edge treatments amid declining revenue from older drugs that must compete with cheaper generics.
Even with the acquisition of Shire, some said Takeda will need to bolster its lineup of experimental therapies to compete in the longer term.
Shire's haemophilia business, for example, is already starting to face strong pressure from a competing drug being marketed by Roche as well as new gene therapies now in development.