Thursday, January 1, 2015

Orkambi in Pregnancy

At the beginning of the month, the FDA approved Orkambi, Vertex's second drug that treats the underlying cause of cystic fibrosis. Unlike Kalydeco, which treats about 5% of the CF population, Orkambi (which is a combination of Kalydeco—ivacaftor—with another ingredient, lumacaftor) could eventually treat 50-60% of CF patients worldwide, which is pretty huge. I have several friends who have already received Orkambi and started taking it. While it's not as universally helpful as Kalydeco and there are some patients who don't see much difference in their health except for becoming more stable, it's still really thrilling to watch it starting to roll out.

Long before Orkambi hit the market, I started getting e-mails from women and occasionally men who were hoping that Orkambi (previously called VX770/809) would help them but wondering about its safety profile in pregnancy. I totally get this, since one of my big concerns before and after Kalydeco was released was how it would effect a fetus, since I had been trying to get pregnant for about a year and a half when I started taking Kalydeco. For a long time I didn't have anything to say to these curious people, because Vertex didn't release any of its data from rodent studies of pregnancy and lactation until Orkambi was FDA approved. Now, however, they have, and since I'm getting this question even more I figured I would make a handy dandy blog post that shared all of the information I've been able to find.

A quick recap: Why I stayed on Kalydeco (and why I can't tell you if you should stay on Orkambi!) while pregnant
(For a more complete picture, read this blog post)

Let me start this post with a big fat disclaimer: I am not on Orkambi, I have never been on Orkambi, and I can't tell you if you should try to get pregnant on it or not.

There are so many factors that go into making huge decisions like these, and the clinical safety data is only one small part of the puzzle. I've heard from women who have decided to stay off Orkambi until they get pregnant and then start it, which is great. Had I been less fertility-challenged than I was, I might have done the same thing with Kalydeco when it was first released. However—and this is a key part of my story—I'd already been trying to conceive for a year and a half when Kalydeco became available, and at that point I was nearly menopausal at twenty-three because my hormone levels were dangerously low due to the stress CF put on my body. I considered it dang good if I had four menstrual cycles a year, which is a condition under which it's next to impossible to get pregnant.

The way things were going, we were staring down the barrel of a long-term infertility problem, and my doctor and I both felt like waiting to start Kalydeco until after I gave birth was unwise because that could potentially be a very long time down the road. Also, although my lung function was high, I had had a very rough and unstable couple of years in which I was hospitalized regularly and spent most of my time feeling very sick. Had my lung function been more stable or my overall health been better, I might have decided to wait.

So I think it's important to remember, if you're in the position of trying to decide whether to roll the dice with a brand-new drug and pregnancy, that there are a lot of factors going into it and that you have to ultimately do what you feel most comfortable with. What I chose to do was not necessarily what my doctor was most comfortable with (see my original blog post, linked above), but it was what my husband and I felt was right after much soul-searching, prayer, and research.

Orkambi's safety data, and why those myths you've heard aren't true

And now to the good stuff: How safe IS Orkambi in pregnancy?

While the VX770/809 trial was happening, there were years' worth of rumors about how unsafe the combination was going to be for pregnancy. The study required two forms of birth control, and had very strict rules about being disqualified from the study if you discovered you were pregnant anyway. Because of this, a lot of people started hypothesizing that 770/809 was extremely dangerous to a fetus and already known to cause birth defects. This always seemed very fishy to me, but at that time Vertex had not released any of the data from its rodent studies, and so I couldn't ever completely dismantle the rumor mill.

However, there are two things it's really important to understand about Orkambi: First, that every drug trial will require birth control. (And if they don't, they're not very ethical, or it's a drug that's been on the market for a long time and is just being used in a new way.) This is for two reasons—because it's highly unethical to try an untested drug on a pregnant human, and because many medications can interfere with hormonal birth control and no researcher wants people accidentally getting pregnant during her study because it turned out that the new drug interacted with a patient's birth control pill. I was offered the chance to be in the original studies for Kalydeco, and the requirements were exactly the same. Two forms of birth control. Immediate disqualification if you were found to be pregnant.

The second thing that's important to understand is something I already said above, but I'll say it again: None of the data from the rodent studies of pregnancy and lactation had been released for Orkambi until it was FDA approved. Therefore, all the rumors that Orkambi caused terrible birth defects were just speculation.

Now that the data has been released, it's very easy to find: It is in every package insert in every box of Orkambi, and also available online here. And guess what? Just like Kalydeco, Orkambi has been given a Category B rating by the FDA, which means it's unlikely to cause harm. Although it hasn't been tested on humans (because, again, that's highly unethical), none of the rodent studies (during which rats and rabbits were given many times the human doses of both lumacaftor and ivacaftor) turned up any birth defects or other issues with the pregnancy, although both drugs cross the placenta and are excreted in breastmilk.

My own experience with Kalydeco is that some doctors are very trusting of the Category B rating, and others (like my own doctor at the time) don't feel like it means much at all without the human data to back it up. However, to put it into perspective, most CF drugs are actually rated Category C (a slightly higher risk of adverse events in pregnancy), including things like pancreatic enzymes. My point there is not that Orkambi is necessarily safer than enzymes, but that almost no CF drug is without some degree of risk in pregnancy.

So what should you do?

Only you, your doctor, and your partner can make that call.

Were I in the same position I was in before starting Kalydeco—infertile, unstable, and frequently ill—I would probably choose to start Orkambi and stay on it during my pregnancy. Personally, I would probably not choose to start Orkambi and then stop it later if I found out I was pregnant; although I did consider doing this with Kalydeco when it was a brand-new drug and not much was known about it, I've since heard several stories of people who stopped Kalydeco for one reason or another, ended up getting really sick, and never were able to get back to the health they'd experienced before once they resumed their Kalydeco. It's a phenomenon my previous doctor noted too—he went so far as to say that he felt like even one missed dose of Kalydeco can have serious adverse effects. I don't know if Orkambi will be the same, but it's similar enough that I personally would probably not risk it, because the beginning of pregnancy is a time when you want your health to be at its peak, not taking a huge hit.

And, before I go, one last thought: I've had several women tell me that it's so much scarier to think of taking Orkambi in pregnancy than Kalydeco, because there are so many anecdotal stories of Kalydeco being safe in pregnancy now. And that's totally true. But it wasn't that way for me, or for the other women who got pregnant on Kalydeco immediately after it was released. There were about 4 of us who all got pregnant very close to each other in the three or four months after Kalydeco hit the market, and with one exception, none of us even found each other until after our babies were born. At the time that I got pregnant with Kate we though I might be the only person in the world who had ever gotten pregnant on Kalydeco. (A few weeks later we learned that there was another woman a few months ahead of me, and after Kate was born I connected with a few more who had gotten pregnant very close to the time that I did.) Kalydeco itself was a totally new quantity in the world of medicine as a whole; nothing like it had ever existed before and nobody had any idea how it might affect a fetus.

So I most certainly do understand how terrifying it is to think about yourself and your baby being medical pioneers in this way. And, as I said before, I really can't speak to what anyone should or shouldn't do, because every situation is shaded in its own unique and specific ways. Still, I hope that this information can help a few ladies out there to have safe, confident pregnancies. CF mamas are some of the bravest, toughest warriors I've ever met!

Why I Chose To Stay On Kalydeco While Pregnant

I frequently get e-mails from women with cystic fibrosis who have gotten pregnant (expectedly or unexpectedly) after starting Kalydeco and are desperate for information and advice about the safety of Kalydeco during pregnancy and breastfeeding. Apparently I'm one of the few Kalydeco mamas out there blogging about the experience, because they all seem to find their way to my blog! (Ironically enough, most of them are from the UK, and literally every single one has told me that she is probably the first UK woman to ever be pregnant on Kalydeco, which is obviously not true. UK cysters, clearly we need to teach your doctors a thing or two!)

Because I get this question so frequently, I figured it was high time that I have post detailing my Kalydeco conception experience and why I chose to stay on a drug with zero human data for pregnancy.

To those who are finding this post by searching about Kalydeco pregnancy, I do so understand the anxiety you're feeling. I got pregnant only a few months after the drug was given FDA approval, and at the time I knew of only one other woman in the world who had gotten pregnant on Kalydeco—and she was only two or three months further along than I was. (Later, I learned that there were one or two women who also got pregnant right around the same time I did, but we didn't know about them until after I'd delivered Kate.) Not only was my pregnancy a (blessed) surprise, but I went into my decision-making process without any anecdotal evidence whatsoever. These days, in addition to the rodent study data that helped me make my choice, there's a wealth of evidence-by-mouth that Kalydeco is fairly safe in both pregnancy and nursing. I can think of at least half a dozen CF mamas who have stayed on Kalydeco through all or most of their pregnancies and now have healthy, happy babies—and many of us have successfully nursed them too (I'm still nursing Kate once daily at 20 months). If you're pregnant or trying to get pregnant and you're on Kalydeco, I HIGHLY recommend joining the Facebook group Cystic Fibrosis Mummies. Not only are there hundreds of women in there who have successfully achieved motherhood in one fashion or another while living with CF, but there are lots of Kalydeco mamas who are happy to share their personal experiences. It's a "secret" Facebook group, but if you're interested in joining drop me a line or message either of the creators, whose information can be found here.

Before I launch into my story, here is a big fat disclaimer: All of this information pertains only to Kalydeco (ivacaftor). I have no experience with any of the combination drugs, including Orkambi (ivacaftor+lumacaftor), and can't vouch for its safety in pregnancy. And, of course, I'm not a doctor or pharmaceutical researcher, so please take this only as my own experience and not medical advice! However, I have done a post specifically about what I know concerning pregnancy and Orkambi because it's a question I get asked so often. You can find that here.

How Kalydeco Got Me Pregnant

Well, okay, my husband helped. ;) However, I've never in my life had anything that resembled a normal 28-day menstrual cycle; ever since I was a teenager my cycles have been extremely long and irregular, and they often stopped completely for months at a time when I got sick (like that time I didn't have a period for nine months and then my hospital pregnancy test was "inconclusive"before I'd ever had sex). I had always suspected that this would spell the doom of my hopes for normal fertility, and I was correct. Before getting pregnant with Kate, we tried for a little over a year and a half with nothing to show for it except the doctor telling me my hormone levels were so low that I was nearly menopausal (at 23!), and that there was no explicable reason for it. Although we could never find any medical evidence for my infertility, and CF specialists still insist that CF does not greatly impair female infertility, it was fairly clear to Mahon and I and all of the doctors who were treating us that my fertility problems were due to the stress that living with CF places on my body.

A few weeks after I started Kalydeco, I suddenly noticed a host of weird PMS symptoms that I'd never had before—and after four years of marriage and a year and a half of infertility (during which I charted my temperature and other fertility signs), I was fairly sure I'd had every symptom in the book. Although I did have a period that month (a very early miscarriage), I had been pregnant, and all of those same symptoms came immediately back the next cycle—my pregnancy with Kate. It was fairly clear that Kalydeco had improved my hormonal balance to the point where I could conceive.

Why I Chose To Stay On Kalydeco During The Pregnancy

Obviously, as soon as I had that positive pregnancy test in hand, the first thought on everyone's mind was whether or not I would stop Kalydeco or remain on it through the pregnancy. As I mentioned above, at that time I had only heard of one woman in the world to stay on Kalydeco during pregnancy, and since she was only a few months along her story didn't even help us much, since there was no telling whether Kalydeco was going to have an effect on her baby yet. My doctors and I had discussed the possibility of a Kalydeco pregnancy when I started the drug, but because we had been infertile for quite some time already and weren't going to be able to start fertility treatments for a few months after I began Kalydeco, we were sure that was a "far in the future" kind of concern and hoped that at that point there might be more information available.

The day that I got my positive test, I called my doctor's office with the news and also spent a lot of that afternoon combing through all the literature on Kalydeco I could find. The only real information available was from the package insert, which touched briefly on the pregnancy and lactation studies they had done with rodents while Kalydeco was in early stages. (It's listed under section 8.1-8.2 in the package insert.) Although Kalydeco was found both to cross the placenta and be excreted in the milk of lactating rodents given Kalydeco, no evidence of teratogenicity (toxicity causing birth defects or other issues with a fetus) was found in the animals studied even at 6-12 times the human dose. Although rodent studies are not perfect and there are many documented cases of humans reacting very differently to drugs than studied rodents, it's still comforting to know that there was no teratogenic effect even at enormous doses—and the rodent trial results were enough to get an FDA Category B labeling in the United States, which is a fairly difficult pregnancy class labeling to get. (Most CF medications are Category C.) All of this information did help me feel a little bit calmer about the possibility of remaining on Kalydeco.

My doctor is extremely conservative when it comes to medication and pregnancy and was very uncomfortable with the idea of me staying on Kalydeco while pregnant, but he was equally uncomfortable with the idea of me going off it. There is a growing body of belief—both in the medical community and the CF community—that going off Kalydeco once you're on it can lead to very fast declines and sometimes permanent lung damage that doesn't reverse even after you resume taking it. We both felt that the early stages of pregnancy were not a good time to risk acute respiratory distress and lung damage. Additionally, because it was so clear that the Kalydeco had altered my hormone levels to make it possible for me to conceive in the first place, my doctor and I were both very worried that stopping the Kalydeco would lead to miscarriage as my hormone levels dropped again.

And lest the above paragraph make it sound like my doctor generally preferred the idea of me staying on Kalydeco to the idea of me going off it, let me clarify. He didn't like either option! ;) We had a long phone conversation about all of the potential problems with either choice. Ultimately, he said that he felt he couldn't even really advise me about what choice to make because they both seemed like such bad options, but he said that he would support me in whichever choice I made. We also discussed potentially going off Kalydeco just for the first trimester (when the risk of birth defects is greatest) and then resuming it, but agreed that that would still carry the risks of serious lung illness and miscarriage.

I spent the rest of the day talking to my husband and doing some serious soul-searching and praying about my options. Ultimately, we both felt peaceful about me staying on Kalydeco, feeling that the risks were much greater to both me and the baby if I was to go off of it.

The Happy Ending

As you can probably tell if you've read my blog for awhile, my pregnancy went very well (despite a host of strange non-CF-related complications) and Kate has always been a normal, healthy baby. She has never appeared to have any negative effects from Kalydeco, despite the fact that I stayed on it through my whole pregnancy and have continued taking it while breastfeeding, which I'm still doing. I also have several friends who have had similarly uneventful experiences with Kalydeco during pregnancy and nursing. In addition, I completely attribute the fact that my lungs were very healthy throughout my pregnancy to Kalydeco, since I was enormously more stable than I had ever been before in my adult life. I am almost certain that had I chosen to stop Kalydeco I would have had a very rough pregnancy in terms of pulmonary health.

I hope that this information is helpful to anyone who might be wrestling with this decision right now! I'd be happy to answer more questions via e-mail (my e-mail is on my blog sidebar), and happy to add any prospective or expecting CF moms to the Facebook group I mentioned above.

Tuesday, May 22, 2012

Welcome To My ImagiNation

Me, age 8
I have always been what you would call "imaginative." Throughout my growing-up years, adults frequently referred to me as having an "overactive imagination." Translation: my imagination was so, ahem, strong that I quite often scared myself silly with the things I dreamed up.

My childhood world was richly peopled with crazy things that I believed with my whole heart. I never had the classic "imaginary friend"; instead, I practically had an imaginary life. I was terrified of my parents' unfinished basement in our first house in Idaho, convinced that monsters lurked behind the looming furnace and hid in the exposed vents and piping in the ceiling (to this day, I harbor a little residual leeriness when it comes to water heater closets and exposed piping). And if there weren't monsters in the basement, well, there were definitely monsters in the closet. Each night when my parents tucked me into bed, I would repeat the incantation, "Please close the closet doors." As long as the door was firmly shut, the monsters couldn't hurt me for the night.

For a long time, I had my own queen-sized water bed as a very young child. That same waterbed still sits at my grandparents' house, and I have to admit that every time I see it I am a little surprised by how much it's shrunk over the years. It looms in my memory as a vast expanse of rolling bed, enormous compared to my tiny body. It sat in the old style of waterbed frame, the kind with those soft pads all around it that always put me in mind of the bumper pads we used in the gutters when I went bowling. And yet: Despite the bed's massiveness, I slept on one tiny piece of it. The piece right up against the edge, to be exact. Practically shoved into the crack between bed and frame. My parents never understood why I wouldn't make better use of my enormous bed and, say, sleep in the middle, like a normal person.

But I couldn't. You see, the Three Bears (yes, those bears) lived on the other side of my bed, in the tiny crack between bed and wall, and every night they crept up to join me on my large mattress. I wasn't exactly afraid of them, but I knew we'd all get along better if I stayed out of their territory. Not once in my whole memory do I have a recollection of a time where I scooted closer to the middle of the bed. Then again, I never got eaten by the Three Bears either, so I guess that proves me right. Right?

While on the subject of sleeping at night, I had a few other quirks, as well. I always had to have a blanket (and preferably a thick one) on me, a preference I retain to this day. In some way I can't quite understand, it made me feel fundamentally safer from one of my greatest fears—kidnapping. I was sure, deep down in my little heart, that I would be safe as long as I was snuggled into a really intimidating blanket. I also had to make sure that blanket was tucked all the way under my chin and pulled up around whichever ear wasn't lying against the pillow. No matter how hot it was outside, that ear had to be covered. I had a deep and abiding fear of somebody coming in the middle of the night to give me "shots in my ears" (for real!), and had to make sure that my ear was never exposed. (Years ago, somebody suggested that maybe this fear came from my many hospitalizations in my first two years of life, where people probably came at me with ear thermometers pretty often.)

And it wasn't just at night that my imagination got out of control. I was horribly afraid of many things, including wolves, rattlesnakes, and any kind of natural disaster. One day in first grade, they announced on the intercom that there was a tornado watch in the area, and that all the children needed to head straight home after school and not hang around playing. As the announcement was read, I was petrified in my seat. I knew that a tornado was coming, that we were all doomed to having our houses sucked away and whirled to Oz, and that I had to get home RIGHT AWAY. As soon as they rang the bell I was off, running home as fast as I could without even waiting for my walking buddy to go with me. And in case you're wondering, no, the tornado never showed.

But the #1 fear of my childhood was a natural disaster of a different stripe: Volcanoes. I don't even remember where this fear cropped up, but sometime in my early childhood, I developed a deep and anxious fear of volcanoes. My sweet young mother decided that the best way to get rid of her child's fear was through education, and so she sat with me and read the whole Childcraft Encyclopedia article on volcanoes, including the story of ParĂ­cutin, a Mexican cinder cone that literally appeared in a farmer's cornfield in 1943 and was 5 stories tall after a week. My terrified little brain latched onto this story, and what it taught me was this: VOLCANOES CAN GROW ANYWHERE! In the Childcraft story, it had said that the Mexican farmer was first alerted to something being amiss when the ground started rumbling and the earth felt hot. Accordingly, I frequently checked the temperature of the ground wherever I was, and I instructed my friends to do the same. I have a vivid memory of me with several friends, feeling the blacktop on the school playground on a summer's day and freaking out that it was hot (and therefore, surely a volcano was on its way). Every night before bed (for years), I prayed that a volcano wouldn't grow under my bed. I frequently had horrible dreams involving hot lava, the most terrifying thing I could conceive of.

I was always afraid that Mount Saint Helens in Washington would blow, and that we would all be destroyed by the lava because there wasn't an ocean between us and the nearest volcano (since water was the only thing I knew of that could stop flowing lava). Somehow, I managed to live in Idaho for 5 years of that phobia without ever realizing that we were living practically on top of one of the world's biggest supervolcanoes.

My imagination trucked along as I grew up. In our first house in North Carolina, I used to sit out on our porch and make up stories about a group of three trees in our back yard. The tallest one I called the King, the prettiest one was the Queen, and a particularly gnarled old dead tree was the evil Grand Vizier, who also happened to be a cannibal. At any given time, I was enmeshed in a story in my head, pretending I was one of the characters from my favorite books or making up new tales of my own.

And eventually, I came to understand that a volcano would not grow under my bed, the likelihood of wolves breaking into my house or a monster lurking in the water heater were slim to none, and the Three Bears probably hadn't actually lived on the other side of my bed.

But that "overactive" imagination is still there. And let's just put it this way: I stay far, far away from scary movies.