TOPIC:

Hi all!
I want to buy Harvoni generic from India or Bangladesh using online pharmacy, but worried about stability of drug after possibly freezing during delivery. In my country winter is cold, and drugs may be frozen at post/customs during several days (or even weeks in worst case). Is Harvoni generic sufficiently stable to withstand such freezing without loss of effectiveness?

I found that sofosbuvir and ledipasvir alone were tested in Europe in stressed conditions (-20 celsius degree e t.c.) and no sufficient changes were observed. (www.ema.europa.eu/docs/en_GB/document_li...3850/WC500177996.pdf):

One commercial scale batch was stored at 50, 5 and -20 ºC for up to 4 weeks. Photostability testing following the ICH guideline Q1B was performed on one commercial scale batch. LDV-AS was also exposed to high temperature in the solid state (100 ºC), and in solution (50 ºC). Samples were also exposed to acidic (1.2 M HCl, 60 ºC), basic (1.2 M NH4OH, 60 ºC) and oxidative (H2O2) forced degradation conditions. The following parameters were tested:appearance, impurities (HPLC), assay (HPLC) and water content (KF). The analytical methods used were the same as for release. The analytical methods used were the same as for release and were stability indicating.No significant changes to any of the measured parameters, other than a minor increase in water content, occurred on storage under long term, accelerated or stressed conditions.

But final product, combined sofosbuvir and ledipasvir in one tablet (Harvoni) have "room temperature below 30 celsius" storage conditions. What is reason for it? Will Harvoni lose effictiveness after freezing? What do you think about it?

Thank you,
Serg

Hello Serg, and welcome to the forum.

If the active pharmaceutical ingredients (Sof & Led) can withstand extremely low temperatures, mixing the with a few inert fillers to make them into pills isn't going to change that (or any other of their) medical property.

Due to uncertainty and a home with no air-con I have stored my sof+dac in the fridge. I am worried that I may have damaged the chemistry by keeping at a temp too low. Thanks in advance for any advice.

Do not worry, your medication will be fine. Please read: fixhepc.com/kunena-2015-11-10/faq.html and the "How do I store my medications" part.

Destruction of chemical APIs occurs by heating rather than cooling.

Here is the FAQ answer:

The original manufacturers of Sofosbuvir, Ledipasvir, Daclatasvir say this in their CMI:

Keep HARVONI tablets in a cool, dry place where it stays below 30°C

Store DAKLINZA tablets in a cool dry place where the temperature stays below 30°C.

More or less all medications say something like this.

For reference:

Sofosbuvir: Melting point. 95-100 ºC
Ledipasvir: Melting Point: 186 - 190ºC
Daclatasvir: Melting Point: 166-172°C

So you could almost certainly store them at > 30 °C but if you follow the < 30 °C recommendations everything should be fine.

The main issue with higher temperatures is that gelatine capsules will melt at 44 °C.

The main issue with moisture is that both capsules and tablets are designed to fall apart in your stomach when they get wet.

Refrigeration will be fine but does create moisture problems. While a fridge is cool and dry the problem occurs when you have warm moist air (room air) and then cool it causing the moisture to condense - you have probably seen this if you put hot food in the fridge with droplets of moisture rapidly replacing the steam on the lid.

You should not freeze the medication although freezing theoretically increases the molecular stability of the APIs, and in fact the NMI certificates found here fixhepc.com/blog/item/16-testing-provisions-patient-safety.html state:

Recommended storage

When not in use, this material should be stored at or below 4 ºC in a closed container in a dry, dark area.

Hello Serg,

I will just go out on a limb and say you should not worry - first read the bit of the FAQs about how to store the medications:

fixhepc.com/kunena-2015-11-10/faq.html

If you think about the science of molecular stability at absolute zero a molecule is stable almost indefinitely because there is no atomic motion and thus no capacity to break down.

Heat can destroy a molecule, cold more of less can not destroy small organic molecules, although large organic molecules like for example egg white can be cooked (denatured) by putting them it into liquid nitrogen. Proteins are on a totally different scale to sofosbuvir, ledipasvir and daclatasvir which exist in a crystalline structure like sugar or salt (neither of which are destroyed by cold). Proteins are denatured because the temperature in which they "expect" to exist determines very complex conformations.

The breakdown of organic matter due to freezing (say with frostbite) relates to large ice crystals rupturing cell membranes. Snap freezing things like embryos and foods works because the ice crystals formed are so small they do not rupture the cell membranes.

Vitamins and co factors are of similar scale to the DAAs and we know that freezing preserves them, where as cooking with heat can damage them.

So in other words severe cold can damage very large complex things, but is unlikely to damage small organic molecules like DAAs.

Note that ledipasvir is by far the most unstable of the 3 common DAAs - it falls apart in chloroform for example.

James, Alsdad - thank you very much!

Today I received answer from Gilead about Harvoni storage conditions. They wrote that for -20 celsius acceptable duration of storage is 28 days. It seems good enough. Text of their answer:

Harvoni tablets do not require any special storage conditions.

Data extrapolated from results of in-house stability studies demonstrate that LDV/SOF tablets are stable when stored in the recommended container system and exposed to a variety of temperatures and relative humidity (RH) conditions beyond those described in the Prescribing Information. A summary of results from these studies is shown in Table 1. The “acceptable duration” solely relates to the stability of the tablets relative to the specified storage conditions, but does not endorse dispensing tablets in alternative packaging or use beyond the expiration date stated on the original packaging.

Table 1: Summary of Storage Conditions and Acceptable Duration for LDV/SOF Tablets

Storage Condition Pack Type Acceptable Duration

25°C (77°F)/60% RH Original bottle 24 months
30°C (86°F)/75% RH Original bottle 24 months
40°C (104°F)/75% RH Original bottle 6 months
5°C (41°F) Original bottle 45 days
25°C (77°F)/80% RH Original bottle 45 days
50°C (122°F) Original bottle 45 days
Open dish 25°C (77°F)/60% RHa No Container 45 days
Open dish 30°C (86°F)/75% RHa No Container 45 days
-20°C (-4°F) Original bottle/No Container 28 days
Light exposure No Container 2-3 days to 3 monthsb

Abbreviations: RH: relative humidity
a Tablets are stored outside of the commercial packaging configuration in an open petri dish.
b Acceptable duration depends on the type of light exposure and ranges from 2-3 days for exposure to full sunlight such as through a window to 3 months for exposure to fluorescent light such as in an office environment.