The recall of injectable recombinant parathyroid hormone (PTH) (Natpara, Takeda) in the United States over safety concerns about the product is gravely affecting the lives of American patients with severe hypoparathyroidism who need replacement PTH therapy to adequately control symptoms.
Approximately 2700 patients in the United States have been affected by the recall of Natpara, according to Takeda. Those who were taking it have had to transition back to controlling their symptoms with just oral medications, including active vitamin D or calcitriol (Rocaltrol, Roche) plus calcium supplements, which has had a negative impact on the management of their disease in most cases, with some patients hospitalized because of severe hypocalcemia.
One patient told Medscape Medical News that even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, individuals can still feel pretty awful because the benefits of the Natpara are subtle — patients just feel better on it. And one report indicates at least 100 patients who had to stop Natpara because of the FDA recall have been hospitalized.
"It's been a rough time for all patients previously on Natpara adjusting to oral medications after they have been on a replacement therapy," endocrinologist Dolores Shoback, MD, University of California San Francisco, told Medscape Medical News in an email.
Aliya Khan, MD, agrees: "This molecule...is life-changing...[It] makes a huge difference in patients' quality of life and in their ability to function normally."
"The FDA in the United States made the recall decision and we have to respect that," added Khan, a professor of clinical medicine at McMaster University in Hamilton, Ontario, Canada.
"We need to address patients' needs and [try to] reinstate it," Khan added, who is the lead author of recent guidelines on the treatment of hypoparathyroidism, and who has received research funding from Takeda and Ascendis Pharma, both of which make injectable PTH.
Kahn also has advice for US endocrinologists who are having to deal with patients who were previously on Natpara and no longer have access to the drug.
She explains how they can transition patients back to other available therapies.
For Severe Hypoparathyroidism, Oral Treatments Are a "Band-Aid"
Hypoparathyroidism is a rare endocrine disorder that affects approximately 60,000 people in the United States. The FDA approved Natpara as an orphan drug and as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism in January 2015.
The FDA issued the recall for Natpara in September, out of concern that rubber particulate matter originating from the rubber septum of the drug's cartridge might be contaminating the product.
But the European Medicines Agency, which approved the product under the brand name Natpar in 2017, has not reached the same decision as the FDA; patients in Europe who qualify for injectable PTH still have access to the drug.
As Khan explained to Medscape Medical News, PTH is critical for the control of calcium and phosphate homeostasis.
When functioning normally, the parathyroid glands are able to regulate blood calcium levels very finely, sensing how much calcium is being resorbed through the kidney, how much is going in and out of bone, how active vitamin D levels are, and the amount the body is absorbing from the bowel and bone. "It's all being very carefully fine-tuned continuously," she said.
Patients with hypoparathyroidism suffer from very low levels of serum calcium, which can, in turn, lead to seizures and cardiac irregularities as well as bronchospasm and even respiratory failure. Magnesium levels can also be dysregulated by hypocalcemia.
"All these are serious results of very low calcium levels," Khan emphasized.
These patients "are also not able to eliminate phosphate through the kidneys so their phosphate levels rise," she added.
Standard treatment for hypoparathyroidism is active vitamin D or calcitriol (Rocaltrol, Roche) plus oral calcium supplements.
However, for patients with severe hypoparathyroidism, for whom injectable PTH is indicated, standard treatment is like a "band-aid" because what they really need is replacement PTH to help them regulate calcium levels as finely as possible, Khan explained.
Hungry Bone Syndrome: Patients Hospitalized for Severe Hypocalcemia
If PTH is stopped abruptly, calcium levels will likely plummet, a phenomenon sometimes referred to as hungry bone syndrome, placing patients at risk for the consequences of severe hypocalcemia, Khan told Medscape Medical News.
(Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia, which is exacerbated by suppressed PTH).
One report suggests at least 100 patients who had to stop Natpara because of the FDA recall had to seek hospitalization to have calcium levels restored intravenously.
And even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, patients can still feel pretty awful.
"When you look at my blood levels on and off Natpara, they look very similar," Danette Astolfi, a former Natpara user in the United States who recently transitioned from the injectable to standard of care, told Medscape Medical News.
"But I felt much, much better on Natpara, so this is an interesting 'wild card' that patients have with this drug — they just feel better on it. They don't have the fatigue, they don’t have the brain fog, they don't have the aches and pains even if their calcium levels are normal," Astolfi said.
So patients who are candidates for injectable PTH therapy are by definition those who do not do very well on standard-of-care calcium and calcitriol.
"With the recall, patients are going back to this regimen they already did not have great success with," Astolfi explained. "And that's the tricky part because if you fall into this category, as I do, there is not much you can do about it."
Astolfi, who is also on the board of directors of the Hypoparathyroidism Association in Pennsylvania, was lucky because she did not have to stop treatment with injectable PTH abruptly.
"I was fortunate. My physician did not want me to stop the drug right away so we had time to develop a discontinuation plan," she noted.
Transitioning Patients Safely to Other Therapies, Including Teriparatide
Khan has advice for endocrinologists dealing with patients who were previously on Natpara and no longer have access to the drug.
"Firstly, endocrinologists need to be aware that when you stop PTH treatment suddenly, patients' need for calcium supplements and calcitriol may be as high as two times what they were on before they started PTH therapy," she noted.
Physicians also need to follow patients closely by monitoring not only calcium and vitamin D levels but also phosphate and magnesium almost daily.
Khan said she does this because it's difficult to predict how much calcium and calcitriol a patient will require and doses will likely have to be titrated up or down based on lab results.
It is noteworthy that a joint statement on the Natpara recall by the Endocrine Society and the American Society of Bone and Mineral Research (ASBMR) also emphasizes these points.
And Khan — as well as the Endocrine Society and ASBMR — also point out that patients may be transitioned from Natpara to teriparatide (Forteo, Eli Lilly), another recombinant form of PTH that is licensed for use in osteoporosis but has not been approved for hypoparathyroidism.
In Khan's experience, patients often do quite well on teriparatide.
The big downside of prescribing teriparatide in the United States, however, is that the drug has to be used off-label, and as such, insurance companies are unlikely to pick up the tab for what is an expensive treatment, she explained.
Furthermore, teriparatide has a very short shelf-life once injected so patients may need to use up to four needles a day to stabilize calcium levels.
If teriparatide is prescribed, subcutaneous injections given in the thigh are recommended for the treatment of hypoparathyroidism, according to the joint Endocrine Society/ASBMR statement.
Takeda Versus the FDA
In the meantime, Takeda says it has been in regular contact with the FDA to try and work out how to bring Natpara back to US patients who require it for symptom control.
Current outstanding issues between the company and FDA involve considerations related to dose accuracy, safety, and supply continuity, which the company hopes will be resolved in a timely manner.
Furthermore, shortly after the recall order, the company created a special use program that continues to support patients previously prescribed Natpara who would otherwise be at extreme risk of serious complications if forced to stop taking the drug.
"Originally intended for an extremely limited number of patients, the special use program has now enrolled approximately 300 patients," Cheryl Schwartz, head, US Hematology & Rare Business Unit, Takeda, said in a letter to members of the US Hypoparathyroidism Association on November 21.
The number is higher than expected and reflects the significant treatment needs of patients with serious disease, Schwartz noted.
"I want to reiterate that we do understand and sincerely regret the impact the Natpara recall is having on patients. We will provide another update as soon as we have more information to share. We continue to work around the clock to find ways to bring Natpara back to the broader hypoparathyroidism community," she added.
"Patient safety always has been, and continues to be, the highest priority for Takeda," she said.
Khan is currently involved in clinical trials evaluating Natpara in Canada (where it is not yet approved).
She was also involved in some of the pivotal studies that helped gain support of the product in the United States and European Union, including REPLACE, which showed that the injectable PTH molecule maintained serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation.
"We now have 8 years of experience with this molecule, so we know that it's safe and effective," Khan emphasized.
Health Canada has not deemed Natpara problematic enough to stop the ongoing research program into injectable PTH therapies there, which is being headed up by Khan at McMaster University.
"The company has not yet applied for approval here, but when they do apply, I am sure they will have fixed this problem by then," Khan said. "And I expect it will be fixed momentarily in the United States, where patients have been most affected."
Asked if she was looking forward to getting Natpara back on track, Astolfi said "absolutely" several times.
"This recall has really had a large impact on our community," she stressed. "And while it's good that critically ill patients have access to the drug through the special use program, we want to get everyone back to their best life and feeling great."
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Cite this: Drug Recall in US Causes Hypoparathyroid Patients Extreme Hardship - Medscape - Dec 02, 2019.