VORAXAZE

Voraxaze( glucarpidase):

Date of Approval: 17^th january 2012.

Mechanism of Action

VORAXAZE (glucarpidase) is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. VORAXAZE converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N¹⁰-methylpteroic acid (DAMPA) and glutamate. VORAXAZE provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.

Pharmacodynamics

Plasma methotrexate concentrations within 48 hours following administration of VORAXAZE can only be reliably measured by a chromatographic method because DAMPA interferes with the immunoassays. Following administration of VORAXAZE 50 Units/kg to patients in Study 1, methotrexate concentration measured by a chromatographic method was reduced by ≥ 97% within 15 minutes in all 22 treatment-evaluable patients, and was maintained at a > 95% reduction up to 8 days in 20 of the 22 patients.

Pharmacokinetics

The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in eight healthy subjects following an intravenous injection of VORAXAZE 50 Units/kg over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by ELISA.

Serum glucarpidase activity levels declined with a mean elimination half-life (t_1/2) of 5.6 hours. The mean Cmax was 3.3 µg/mL and the mean area under the curve (AUC_0-inf) was 23.3 µg·h/mL. The mean systemic clearance (CL) was 7.5 mL/min. The mean volume of distribution (V_d) was 3.6 L, suggesting that glucarpidase distribution is restricted to plasma volume. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer t_1/2 of 9 hours.

Among the 290 patients included in the safety evaluation of VORAXAZE, there were 8 deaths within 30 days of VORAXAZE exposure that were not related to progressive disease. Twenty-one of 290 patients (7%) experienced adverse reactions that were assessed as related to VORAXAZE. Most were Grade 1 or 2 events. One patient experienced related Grade 3 flushing. The most common related adverse reactions that were not hematologic, hepatic or renal events were paresthesia, flushing, and nausea and/or vomiting, which each occurred in 2% of patients (Table 1).

Table 1: Per Patient Incidence of Grade 1 and 2 Adverse Reactions Assessed as Possibly, Probably, or Definitely Related to VORAXAZE Excluding Hematologic, Hepatic, or Renal Adverse Reactions

Adverse Reaction	N= 290 n (%)
Paresthesias	7 (2%)
Flushing1,2	5 (2%)
Nausea/Vomiting	5 (2%)
Headache	2 (1%)
Hypotension	2 (1%)
Blurred Vision	1 ( < 1%)
Diarrhea	1 ( < 1%)
Hypersensitivity	1 ( < 1%)
Hypertension	1 ( < 1%)
Rash	1 ( < 1%)
Throat irritation/Throat tightness	1 ( < 1%)
Tremor	1 ( < 1%)
1 This incidence includes the following terms: flushing, feeling hot, burning sensation. 2 One of these reactions was classified as Grade 3 in severity.

Immunogenicity

In clinical studies, 96 patients were evaluated for anti-glucarpidase antibodies. One (n=78) or two (n=18) doses of VORAXAZE were administered intravenously to these patients. Sixteen patients (17%) developed anti-glucarpidase antibodies following VORAXAZE administration. Antibody titers were determined using a validated bridging enzyme-linked immunosorbent assay (ELISA) for anti-glucarpidase antibodies. Twelve of the 16 patients who developed anti-glucarpidase antibodies had received a single dose of VORAXAZE, and four of the patients had received two doses of VORAXAZE.

Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to VORAXAZE with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

Use of VORAXAZE with Leucovorin

Leucovorin is a substrate for VORAXAZE. Do not administer leucovorin within 2 hours before or after a dose of VORAXAZE. No dose adjustment is recommended for the continuing leucovorin regimen because the leucovorin dose is based on the patient¡¦s pre-VORAXAZE methotrexate concentration

CONTRAINDICATIONS

None

FDA APPROVED USES:

The U.S. Food and Drug Administration today approved Voraxaze (glucarpidase) to treat patients with toxic levels of methotrexate in their blood due to kidney fa

US VISA COUNSALTE OFFICE AT MUMBAI

US Visa Process at the new US consulate Office @ Bandra Kurla Complex (BKC)

For all who are planning to apply for US visa or others thinking about it or who are just plain curious to know about "What happens at the consulate office?" - Read on then :) !!
Last week my company processed my US visa related to my work. It was a nice experience. After struggling to get the visa appointment, finally we got one in November early morning 9 am. Being in Pune I was suppose to drive to Mumbai consulate office early morning.

Just wanted to share the visa processing experience - What happens at the consulate office - with all of you !!

Lets go through them step by step.

1. I reached the American Consulate General Mumbai office at 7:30 am, the new office at BKC (Bandra Kurla Complex). Since it moved this November 18th 2011. The new BKC address is as follows:

   C-49, G-Block,Bandra Kurla Complex,Bandra (East), Mumbai 400051.

2. Since the appointment was a 9 am, I had my breakfast at a nearby restaurant.
3. I picked up all my documents and joined the queue at 8:15am. It was a long queue.
4. After this point, no one without visa appointment confirmation are allowed.
5. The office opens at sharp 9am.
6. By 8:45 we had some Consulate officers come out and announced..
   "please keep following document ready"

   1. Original Passport.
   2. Confirmation of appointment letter.
   3. Invitation letter from the company.
   4. HDFC receipt original.

   
   
7. They verified all the 4 documents. HDFC receipt has a small barcode sticker, they remove one from the set and paste it on the back side of your passport.
8. After this the main consulate office gate open and you are allowed to go in.
9. Immediately entering the Consulate office main door, you are placed in a queue, where you need to submit all the 4 documents. They scan the barcode of appointment confirmation. This generates another barcode. They paste that receipt on the  front of your passport. This receipt also has the token number. Mine was N266.
10. Once this is done, they return you your passport and all your documents. You are now asked to proceed for the security check.
11. This is the general security check just like the one that we go through at the airport. You need to place all your belongings ie: document folder, watch, belt etc in the box and put that box through a scanner and stand in queue for body check.
12. After your turn comes, you will be scanned by the Consulate security officer. once this is done everything is in place now.
13. You need to collect your belongings and rush towards the counters, fearing your token will be called out.
14. After you leave the security room, you will be rushed to an office where actual interview happens.
15. Once you enter the door, you will asked for type of visa you are applying and will be directed accordingly to a proper queue.
16. In your new queue, First thing they do is Biometrics. They scan your left hand's 4 fingers excluding your thumb, then same with right hand. then lastly both of ur thumb impressions together.
17. Then you will be asked to sit and wait for your token to be called out.
18. Its a big hall with lotts of seating arrangement. Interview counters are exactly opposite to the seating arrangements.
19. You will see 10 counters labelled 31 32, 33 upto 40. For different Visa type counter numbers may differ.
20. There are two LCD screens displaying the next token number and the counter that token number is suppose to go to. i.e. something like

         Counter 33
         Token N256

21. Also at the top of each counter, the current processing token number as well as next token number to be processed is displayed.
22. All interviewing officers are foreigners. All Americans.
23. Once your token number is displayed and called out on the LCD display, You are supposed to head straight towards that counter and stand in queue. Unless the interviewer calls you at the window. Queue is generally quiet short, couple of people.
24. Finally the time arrives and you are called by the interviewer and you head straight for that counter window.
25. Counter has a big glass window completely bullet proof. At the right hand side you will notice a Speaker. The interviewer generally has a mike through which he speaks out load, you need to pay attention to the speaker to understand the questions asked.
26. At the counter hand over only the passport. If You have re-issued and gotten a new passport, carry both the old and new passport and hand  over both to the interviewing officer. Especially if you have visas on your old passport.
27. Now the Question and answer session starts. This will typically last for 5-10mins. depending totally on the interviewer and how you answer his questions.
28. I will only list out here question that were asked to me.

     Q1. Why do you want to go to US.
     Q2. Whose going to finance you.
     Q3. Where do you work.
     Q4. What do you work on.
     Q5. How much do you earn.
     Q6. Why is it that you are traveling to US for 1st time in so many years.
     Q7. Where will you stay in US.
     Q8. How long you will be staying in US.
     Q9  Why xyz months/week.
     Q10. Question about my Europe and UK visa
     Q11. Where are you going in US ( city and state name in US).
     Q12. what are you going to bring back for your team from US ( in terms of work /knowledge base).

29. After all those massive  questions and answer sessions ends, if the interviewer keeps you passport then its all done. Yipeeeee !!.
    Your have successfully handled it. Within 3 days your passport along with US visa will be delivered by Bluedart to your mailing address. Also you have an option to collect the same by 5pm same day at the Mumbai VFS office. You get an SMS about this in couple of hours as well.
30. If for some other reason the interviewer hands your passport back to you, then you did not clear the interview "According to the Interviewer". So you will have to apply again. Don't get disheartened because its complete luck and the officers mood/questions. cheer up and apply a second time.
31. After this you can take the exit door and leave the consulate office.

Some odd things to keep in mind :-
1. Carry all your documents like education certificates, work related documents, identity proof etc. Originals as well as a copy. Trust me you don't want to run at the last moment. They didn't ask me for any documents, that would not be the case always.
2. Reach early. Even though its mentioned that your appointment is at 9 am, 10, 11 etc .. still try to go there atleast 45 min early. There are lottts of people having an appointment the same day same time. So early you reach, closer you are.
3. Don't carry bagpacks, suitcase, rack etc . they are not allowed inside.
4. The new consulate office is very near to the TRIDENT hotel. I mentioned it incase you need a landmark. Consulate is a landmark in itself .. so don't worrry. lotts of people go to work in BKC, also people jogging early morning .. all are aware of the place :) so be relaxed !!
5. Last but not the least. Smile, Be Confident and come back with nice experience :) that is all that matters the most !!

Now Geared with all the new experience  about US visa processing, share your experience with your close ones and just blog it - like the way I did !!

All the best :) !

Evaluation of strip and blister packaging

Procedure for Leak testing of strips / blisters

1.0 OBJECTIVE
To lay down a procedure for leak testing of strips / blisters.
2.0 SCOPE
All packing areas.
3.0 RESPONSIBILITY
Production officer.
4.0 ACCOUNTABILITY
Production executive
5.0 PROCEDURE
5.1 Take the required number of strips / blisters as mentioned in the Annexure – I. Check the quality of strips/ blisters for any damages.
5.2 Tie the collected strips / blisters with a rubber band.
5.3 Ensure that all strips / blisters are dipped in water and close the lid.
5.4 Connect opening of the desiccator to the vacuum pump.
5.5 Apply a vacuum of 300 mm of Hg and close the knob of the desiccator.
5.6 Keep the vacuum for 30sec.
5.7 Release the vacuum by opening the knob of the desiccator slowly and open the lid remove the strips / blisters.
5.8 Wipe out the traces of water from the strips / blisters by using lint free duster .
5.9 Open the pocket of strips by using scissors to remove the tablets / capsules.
5.10 Open the blisters manually.
5.11 Check for any traces of water inside the strips / blisters.
5.12 Number of tablets or capsules, which have become wet, should not be more than 1%. If the leakage is more than the above percentage repeat the leak test.
5.13 Record it in the respective batch packing record, with signature and date.
ANNEXURE -I


Note:
1. Perform leak test at the starting of blistering / strip sealing, operation.
2. If there is machine break down more than 1/2 hour perform leak test immediately after starting the operation.
3. Whenever leakage observed during leak test, ensure that rectification is done.
4. If leak test failure is occurring repeatedly, bring to the notice of Executive / Sr. Executive for corrective action.