Natpara Recall

Sept 15, 2021

 

Takeda's letter to Healthcare Providers: see below. 

My summary: A Prior Approval Supplement (PAS) that proposes a new septum and new needle to address the rubber particle issue has been submitted to the FDA.  Approval would resolve the rubber particle issue.  The approval process typically takes 4-6 months but may take longer. 

The letter, however, also notes the additional supply and manufacturing issue that is a different problem and that also needs to be solved to bring NATPARA back on the market. 

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Dear Healthcare Provider,

The purpose of this communication is to provide a regulatory filing update for NATPARA® (parathyroid hormone) for Injection in the US. No action is required by you, however we are sharing this information for your awareness because your patient(s) enrolled in the Special Use Program (SUP), as well as many patients previously prescribed NATPARA, will also be receiving this update.

Takeda has submitted a Prior Approval Supplement (PAS) to the US Food & Drug Administration (FDA) as the next step in the Company’s efforts to address the issue of rubber particulates originating from the rubber septum of the NATPARA cartridge that led to the US recall in September 2019. The submission proposes device component changes that include a new septum and new needle. US regulatory approval of the PAS is a critical step to bringing NATPARA back in the US, as the proposed changes are required to enable US patient use per the approved NATPARA labeling, which includes 14-day administration.

As our leadership team shared during the April 2021 community call, there are a few potential regulatory outcomes from FDA’s review of this submission. Once FDA completes their review, the outcomes could include: 1) regulatory approval; 2) regulatory feedback that may require changes to our approach; or 3) significant regulatory feedback that may lead to starting the process over again. While Takeda is optimistic about the approach we have submitted to FDA, the timeline and outcome are still uncertain.

The next step in the regulatory process is for FDA to review our submission, which typically takes four to six (4-6) months after a PAS has been filed. This timeline could be extended should additional data or alternative proposals be required following regulatory discussions.

In addition, the supply and manufacturing issues that we described during the April call are separate from the issue that led to the US recall and remain complex. As we continue to work with urgency to address those issues, it is important to underscore that a potential FDA approval of the PAS is not the only variable that will determine how soon we can return NATPARA to the broader patient community. Our ability to provide a stable and consistent supply of NATPARA will also be a critical factor and remains an area of focus. Patients enrolled in the SUP continue to have access to NATPARA in the US through that Program.

We will plan to provide another update that includes the anticipated regulatory review timeline and a status update on the manufacturing/supply issues before the end of the 2021 calendar year. We understand how difficult the past two years have been for the community, and we remain committed to keeping you updated as we make progress in our efforts to bring NATPARA back.

 

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Sept 24, 2019

 

Forteo: some details. 

**Note that Forteo is not FDA approved for hypoparathyroidism**

The Forteo pen is set to give a fixed dose of 20 microgram, which comes in a volume of 80 microliters (this is the dose that patients for osteoporosis need).

For hypoparathyroidism, variable dosing is necessary and is achieved by drawing Forteo from the cartridge with an insulin syringe and needle (which is not FDA approved).

Insulin is dosed by “units”; therefore, insulin syringes are marked with “units.”

1 unit = 10 microliters.

10 microliters of Forteo = 2.5 microgram of Forteo = 1 unit

80 microliters of Forteo = 20 microgram of Forteo = 8 units

When used for hypoparathyroidism (off label), Forteo should be given at least twice daily (some might need three injections per day, roughly 8 hours apart).  The more frequently Forteo is administered, the less Forteo per day is needed for most patients.

On a molar basis, 1 microgram of Forteo corresponds to about 2.3 micrograms of Natpara.

A person who was on 50 micrograms of Natpara, might get away with 10 micrograms of Forteo (4 units) twice daily.  Frequent blood tests are needed to adjust the dose of Forteo (and/or calcium/calcitriol).

Forteo’s website contains a warning: Do not transfer the medicine from the FORTEO delivery device to a syringe. This can result in taking the wrong dose of FORTEO.

 

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Sept 19, 2019

Here is the Joint American Society for Bone and Mineral Research (ASBMR) – Endocrine Society Guidance on Transitioning Hypoparathyroidism Patients from NATPARA®.

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Sept 11, 2019

Forteo

A few words about Forteo (recombinant human PTH[1-34], also called teriparatide).

In the United States, Forteo is approved for the treatment of osteoporosis.  It comes with a black box warning about the risk of osteosarcoma (which is well known to users of Natpara).  Forteo’s use is restricted to two years.

The cost of Forteo has increased over the last few years and is now around $30,000 per year.  It is self-administered with a pen and comes only in one strength; each shot contains 20 mcg of Forteo (which, on a molar basis, is similar to 45 mcg Natpara).

Forteo is produced by Lilly.  Its patent ran out in August 2019, and it is, therefore, possible that another company will start producing generic teriparatide.  When a patent runs out and the drug is produced as a generic, often (but not always) prices go down dramatically. Currently, there is no generic teriparatide approved or available in the US.

Different insurance companies handle the authorization of Forteo for patients with hypoparathyroidism differently.  Some approve it without prior authorization (PA).  Others require PA, detailed patient information, and the reason for the use.  Some approve it; others do not.

If the transition to Forteo is desired, the patient should call the insurance and ask if it is covered. Another way to find out if your insurance company will approve Forteo is to have your endocrinologist write a script for Forteo and send it to your pharmacy.  It is advisable that you call your pharmacist as they have to enter the request.  You will find out if your insurance needs a PA or not.  If it does, you will have to tell your endocrinologist’s office so that they can initiate the PA.  

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Sept 11, 2019

Here is a letter I sent to insurance companies (your doctor should edit it to reflect your situation):

To Whom It May Concern:

xxxx has chronic hypoparathyroidism, a disease of low parathyroid hormone (PTH) that leads to low calcium (hypocalcemia) and other abnormalities.  Hypocalcemia can lead to mild symptoms or to severe symptoms requiring hospitalization and i.v. calcium. 

Xxxx;s hypoparathyroidism was not well controlled on oral calcium and calcitriol.  She was, therefore, started on PTH replacement therapy with Natpara several years ago.  Treatment with Natpara (PTH[1-84]) has been very successful, and the patient has had significantly fewer episodes of hypocalcemia.  She is on 50 mcg Natpara daily.

Takeda, the sole producer of Natpara, (temporarily) recalled Natpara from the US market on September 6th, 2019, and xxxx will run out of Natpara soon.

This leaves xxxx in a potentially dangerous situation: when Natpara is suddenly discontinued, some patients might develop a transient increase in pre-Natpara calcium and calcitriol requirements.  That might lead to profound hypocalcemia with tetany requiring Emergency Room treatment.

But, there is an alternative. Forteo (teriparatide) is also an injectable form of PTH, PTH(1-34), and has been successfully used in clinical trials at the NIH for hypoparathyroidism.  Forteo is approved for osteoporosis, but for not hypoparathyroidism in the US.

To avoid the complication of hypocalcemia, I want to start xxxx on Forteo 20 mcg daily sc as soon as possible so that she does not have a gap in her PTH treatment.

Please approve Forteo on a compassionate use basis for this patient.

Let me know if you have any questions.

Sincerely,

zzzz, MD

 

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Sept 8th, 2019

The recall of Natpara in the US has caused significant concerns and uncertainties for patients with hypoparathyroidism who are currently on Natpara (PTH1-84) and their providers. 

The recall notice can be found here

The reason for the recall is the observation of some tiny but visible rubber particles in the Natpara solution. These particles originate from the rubber septum of the cartridge, which is punctured by the replaceable cartridge needle each time an injection is made. When the septum is punctured, small pieces of rubber may detach into the solution.

What can be done?

I see the following issues and options.  These are my personal opinions and are in no way intended to be professional management recommendations.

  1. Patients and providers will have to decide whether to continue Natpara until the available stock of Natpara has been exhausted.

The European FDA equivalent (EMA) has decided not to recall Natpar (that is the trade name of Natpara in Europe), while Takeda is looking for a fix. That is a sign that the risk-benefit assessment differs between regulatory agencies in Europe and the United States.

2. Transition to calcium/calcitriol.  When stopping Natpara and switching to oral calcium and calcitriol, some patients transiently require much higher doses of calcium/calcitriol than before starting Natpara. We cannot predict who will need higher doses and for how long.  The transient increase in calcium/calcitriol requirements has also been described by Drs. Gafni and Collins in 2015 (J Bone Miner Res. 2015 Nov;30(11):2112-8).
One possible way of transitioning to calcium/calcitriol:

Start 12 hours after the last Natpara injection with double (or triple) the pre-Natpara dose of calcitriol and the (unchanged) pre-Natpara calcium dose.

Check serum calcium and albumin often (every two days?) and adjust the dose of calcitriol (and calcium) accordingly.

I once tapered Natpara instead of stopping it abruptly but found that this approach required much more extended times of intense blood calcium monitoring.

3. Transition to Forteo (PTH1-34). PTH1-34 has been used for hypoparathyroidism in clinical trials at the NIH by Dr. Karen Winer and colleagues, giving us ample data on it.  However, Forteo’s effect of increasing blood calcium is shorter-lived than Natpara’s, and it is not approved for hypoparathyroidism.  Therefore, twice-daily injections are typically necessary; pre-authorization requests to the insurance companies have to be dealt with. 

Forteo is only 34 amino acids long compared to the 84 amino acids of Natpara.  The molecular weight of Forteo is 2.29-fold smaller than that of Natpara. Practically, this means you have to divide the microgram (mcg) of Natpara by 2.29 to get the equivalent dose of Forteo.
For example, 100 mcg of Natpara is around 44 mcg of Forteo. But if Forteo is given twice daily, a lower total daily dose of it is needed (about 50%) compared to once-daily.  Forteo comes in doses of 20 mcg.