Helixate NexGen 2000 IU

Helixate NexGen 2000 IU powder and solvent for solution for injection

Recombinant coagulation factor VIII (octocog alfa)

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or your pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Helixate NexGen 2000 IU is and what it is used for


• 2. Before you use Helixate NexGen 2000 IU


• 3. How to use Helixate NexGen 2000 IU


• 4. Possible side effects


• 5. How to store Helixate NexGen 2000 IU


• 6. Further information

WHAT Helixate NexGen 2000 IU IS AND WHAT IT IS USED FOR

Helixate NexGen 2000 IU belongs to a pharmacotherapeutic group called blood coagulation Factor VIII (ATC-Code B02B D02).

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

This preparation does not contain von Willebrand factor and is therefore not indicated in von Willebrand's disease.

One vial with powder for solution for injection nominally contains 2000 IU octocog alfa (IU equals International Units). After reconstitution with the appropriate volume of solvent (water for injections), each vial contains octocog alfa 400 IU/ml.

BEFORE YOU USE Helixate NexGen 2000 IU

Do not use Helixate NexGen 2000 IU if you are allergic (hypersensitive) to octocog alfa, to mouse or hamster protein or to any of the other ingredients of Helixate NexGen 2000 IU.

If you are unsure about this, ask your doctor.

Take special care with Helixate NexGen 2000 IU as there is a rare chance that you may experience an anaphylactic reaction (a severe, sudden allergic reaction). If you experience tightness in the chest, feeling dizzy, feeling sick or faint, or experience dizziness on standing, you may be experiencing an allergic reaction to Helixate NexGen 2000 IU. If this occurs, stop administering the product immediately and seek medical advice.

Your doctor may wish to carry out tests to ensure that your current dose of Helixate NexGen 2000 IU is sufficient to reach and maintain adequate factor VIII levels.

If your bleeding is not being controlled with Helixate NexGen 2000 IU, consult your doctor immediately. You may have developed factor VIII inhibitors and your doctor may wish to carry out tests to confirm this. Factor VIII inhibitors are antibodies in the blood which block the factor VIII you are using. This makes factor VIII less effective in controlling bleeding.

If you have previously developed a factor VIII inhibitor and you switch factor VIII products, you may be at risk of your inhibitor coming back.

Using other medicines

Interactions with other medicines are not known. However, please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Based on the rare occurrence of haemophilia A in women, experience regarding the use of Helixate NexGen 2000 IU during pregnancy and breast-feeding is not available. Therefore, if you are pregnant or breast-feeding consult your doctor before using this product.

Driving and using machines

No effects on the ability to drive or use machines have been observed.

Important information about some of the ingredients of Helixate NexGen 2000 IU

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium-free”.

HOW TO USE Helixate NexGen 2000 IU

Helixate NexGen 2000 IU is intended for intravenous administration only and must be administered immediately after reconstitution. Aseptic conditions (meaning clean and germ free) are required during reconstitution and administration. Use only the medical devices for reconstitution and administration provided with each package of Helixate NexGen 2000 IU. Helixate NexGen 2000 IU must not be mixed with other infusion solutions. Do not use solutions containing visible particles or that are cloudy. Follow the directions given by your doctor closely and use the instructions below as a guide:

• 1. Wash hands thoroughly using soap and warm water.


• 2. Warm both unopened vials in your hands to a comfortable temperature (do not exceed 37 °C).


• 3. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an aseptic solution and allowed to dry prior to opening the Mix2Vial package.

• 4. Open the Mix2Vial package by peeling away the lid. Do not remove the Mix2Vial from the blister package!

• 5. Place the solvent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper.

• 6. Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set.

• 7. Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial.

• 8. With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew the set carefully into two pieces. Discard the solvent vial with the blue Mix2Vial adapter attached.

• 9. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake.

• 10. Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vial´s Luer Lock fitting. Inject air into the product vial.

• 11. While keeping the syringe plunger pressed, invert the system upside down and draw the solution into the syringe by pulling the plunger back slowly.

• 12. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe. Hold the syringe upright and push the plunger until no air is left in the syringe.


• 13. Apply a tourniquet.


• 14. Determine the point of injection and prepare antiseptically.


• 15. Puncture the vein and secure the venipuncture set with a plaster.


• 16 Let blood flow back to the open end of the venipuncture set and then attach the syringe with the solution. Make sure that no blood enters the syringe.


• 17. Remove tourniquet.


• 18. Inject the solution intravenously over several minutes, keeping an eye on the position of the needle. The rate of administration should be determined by the patient’s comfort (maximum rate of infusion: 2 ml/min).


• 19. If a further dose needs to be administered, use a new syringe with product reconstituted as described above.


• 20. If no further dose is required, remove the venipuncture set and syringe. Hold a swab firmly over the injection site on the outstretched arm for approx. 2 minutes. Finally, apply a small pressure dressing to the wound.

The amount of Helixate NexGen 2000 IU you should use and how often you use it depends on many factors such as your weight, the severity of your haemophilia, the site and extent of bleeding, the amount of factor VIII inhibitors that you may have and the factor VIII level required.

Your doctor will calculate the dose of Helixate NexGen 2000 IU and how frequently you should use it to get the necessary level of factor VIII activity in your blood. He will do this according to your particular needs using the
formulae below.

I. Required IU = body weight (kg) × desired factor VIII rise as % of normal × 0.5

II. Expected factor VIII rise as % of normal = 2 × administered IU ÷ bodyweight in kg

The following information provides a guide for factor VIII minimum blood levels. In the case of the haemorrhagic events listed, the factor VIII activity should not fall below the given level (in % of normal) in the corresponding period:

Degree of haemorrhage : Factor VIII level required (% or IU/dl) : Frequency of doses in hours; duration of therapy in days

Early haemathrosis, muscle bleed or oral bleed : 20 to 40 : Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.

More extensive haemathrosis, muscle bleed or haematoma : 30 to 60 : Repeat infusion every 12 to 24 hours for 3 to 4 days or more until pain and disability are resolved.

Life-threatening bleeds such as intracranial bleed, throat bleed, severe abdominal bleed : 60 to 100 : Repeat infusion every 8 to 24 hours until threat is resolved.

Type of surgical procedure : Factor VIII level required (% or IU/dl) : Frequency of doses in hours; duration of therapy in days

Minor, including tooth extraction : 30 to 60 : Every 24 hours for at least 1 day until healing is achieved.

Major : 80 to 100 (pre-and post-operatively) : a) By bolus infusions. Repeat infusion every 8 to 24 hours until adequate wound healing occurs, then continue with therapy for at least another 7 days to maintain a factor VIII activity of 30 to 60 %. b) By continuous infusion. Raise factor VIII activity pre-surgery with an initial bolus infusion and immediately follow with continuous infusion (in IU/kg/h) adjusting according to patient’s daily clearance and desired factor VIII levels for at least 7 days.

Your doctor should always adapt the amount of Helixate NexGen 2000 IU to be administered and the frequency of administration according to the clinical effectiveness in your individual case. Under certain circumstances larger amounts than those calculated may be required, especially in the case of the initial dose.

If you are using Helixate NexGen 2000 IU to prevent bleeding (prophylaxis), your doctor will calculate the dose for you. This will usually be in the range of 20 to 60 IU of octocog alfa per kg of body weight, administered at intervals of 2 to 3 days. However, in some cases, especially younger patients, shorter dose intervals or higher doses may be necessary.

Although dosage can be estimated by the calculations presented above, it is strongly recommended that appropriate laboratory tests be performed on your plasma at suitable intervals to ensure that adequate factor VIII levels have been reached and are maintained. In the case of major surgical interventions in particular, a precise monitoring of the substitution therapy by means of coagulation analysis is indispensable.

If the factor VIII level of your plasma fails to reach expected levels, or if bleeding is not controlled after apparently adequate dosage, the presence of factor VIII inhibitors should be suspected. By appropriate laboratory procedures, the presence of factor VIII inhibitors must be checked and quantified by an experienced doctor.

If you have the impression that the effect of Helixate NexGen 2000 IU is too strong or too weak, talk to your doctor.

Patients with inhibitors

If you have been informed by your doctor that you have developed factor VIII inhibitors you will possibly be required to use a larger amount of Helixate NexGen than previously to control a bleeding. If this dose does not control your bleeding your doctor may consider the use of an additional product, factor VIIa concentrate or (activated) prothrombin complex concentrate. Do not increase the dose of Helixate NexGen you use to control your bleeding without consulting your doctor. Speak to your doctor if you would like further information on this.

These therapies should be directed by doctors with experience in the care of patients with haemophilia A.

Helixate NexGen 2000 IU should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level (maximal rate of infusion: 2 ml/min).

Your doctor will tell you, how often and at what intervals Helixate NexGen 2000 IU is to be administered.

Usually, the substitution therapy with Helixate NexGen 2000 IU is a life-time treatment.

If you use more Helixate NexGen 2000 IU than you should

No symptoms of overdosage with recombinant coagulation factor VIII have been reported.

If you have used more Helixate NexGen 2000 IU than you should, please inform your doctor.

If you forget to use Helixate NexGen 2000 IU

• Proceed with the next administration immediately and continue at regular intervals as advised by your doctor.


• Do not take a double dose to make up for a forgotten dose.

If you stop using Helixate NexGen 2000 IU

Do not stop using Helixate NexGen 2000 IU without consulting your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, Helixate NexGen 2000 IU can cause side effects, although not everybody gets them.

The frequency of possible side effects listed below is defined using the following convention:

very common (affects more than 1 user in 10)

common (affects 1 to 10 users in 100)

uncommon (affects 1 to 10 users in 1,000)

rare (affects 1 to 10 users in 10,000)

very rare (affects less than 1 user in 10,000)

not known (frequency cannot be estimated from the available data).

Side effects where frequency is common:

You may notice any of the following side effects after administration of Helixate NexGen 2000 IU:

• rash/itchy rash


• local reactions at the injection site (e.g. burning sensation, temporary redness)

Side effects where frequency is rare:

You may notice any of the following side effects after administration of Helixate NexGen 2000 IU:

• hypersensitivity reactions (e.g. tightness of the chest/general feeling of being unwell, dizziness and nausea and mildly reduced blood pressure, which may make you feel faint upon standing)


• fever.

Furthermore, the possibility of an anaphylactic shock cannot be completely excluded. If you notice any of the following symptoms during injection/infusion:

• chest tightness/general feeling of being unwell


• dizziness


• mild hypotension (mildly reduced blood pressure, which may make you feel faint upon standing)


• nausea

this can constitute an early warning for hypersensitivity and anaphylactic reactions. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately. Please consult your doctor immediately.

During studies, no patient developed clinically relevant antibody titres against the trace amounts of mouse protein and hamster protein present in the preparation. However, the possibility of allergic reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in certain predisposed patients.

The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the management of individuals with haemophilia A. In studies with recombinant factor VIII preparations, development of inhibitors is predominantly observed in previously untreated haemophiliacs.

You should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.

In clinical studies, Helixate NexGen has been used in the treatment of bleeding episodes in 37 previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP patients treated with Helixate NexGen developed inhibitors: Overall 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU. The median number of exposure days at the time of inhibitor detection in these patients was 9 days (range 3 - 18 days).

The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more than 20 exposure days in post-study follow-up and one of them developed a low titre inhibitor. The fifth patient was lost to follow-up.

In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure days), followed over four years, no de-novo inhibitors were observed.

In extensive post-registration studies with Helixate NexGen, involving more than 1000 patients the following was observed: Less than 0.2% PTP developed de-novo inhibitors. In a subset defined as having less than 20 exposure days at study entry, less than 11% developed de-novo inhibitors.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

HOW TO STORE Helixate NexGen 2000 IU

Keep out of the reach and sight of children.

Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vials in the outer carton in order to protect from light.

You may store the product when kept in its outer carton at ambient room temperature (up to 25°C) for a single period of up to 3 months. In this case, the product expires at the end of this 3-month period; you must note the new expiry date on the top of the outer carton.

Do not refrigerate the solution after reconstitution. The reconstituted solution should be used immediately. This product is for single use only. Any unused solution must be discarded.

Do not use Helixate NexGen 2000 IU after the expiry date which is stated on labels and cartons. The expiry date refers to the last day of that month.

Do not use Helixate NexGen 2000 IU if you notice any particles or the solution is cloudy.

Further Information

What Helixate NexGen 2000 IU contains

Powder:

The active substance is recombinant coagulation factor VIII (octocog alfa).

The other ingredients are glycine, sodium chloride, calcium chloride, histidine, polysorbate 80, and sucrose.

Solvent:

Water for injections.

What Helixate NexGen 2000 IU looks like and content of the pack

Helixate NexGen 2000 IU is provided as a powder and solvent for solution for injection and is a dry white to slightly yellow powder or cake. After reconstitution the solution is clear. Medical devices for reconstitution and administration are provided with each package of Helixate NexGen 2000 IU.

Marketing Authorisation Holder:

Bayer Schering Pharma AG

13342 Berlin

Germany

Manufacturer:

Bayer HealthCare Manufacturing S.r.l.

Via delle Groane 126

20024 Garbagnate Milanese (MI)

Italy

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom

CSL Behring UK Limited

Tel:+44-(0)1444 447400

This leaflet was last approved in 03/2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu.

Paraplatin

Generic Name: Carboplatin
Class: Antineoplastic Agents
VA Class: AN900
CAS Number: 41575-94-4

• 
  

  Use only under the supervision of a qualified clinician experienced in the use of cytotoxic therapy.¹ Use only when adequate treatment facilities for appropriate management of therapy and complications are available.¹

  
  


• 
  

  Dose-related bone marrow suppression may result in infection and/or bleeding.¹ Anemia may be cumulative and may require transfusion support.¹

  
  


• 
  

  Vomiting is a common adverse effect.^{1 201}

  
  


• 
  

  Anaphylactic-like reactions may occur within minutes of administration.¹ Administer epinephrine, corticosteroids, and/or antihistamines to relieve symptoms.¹

  
  

Introduction

Antineoplastic agent; platinum-containing compound.^{1 2 3 4 5 6 92 93}

Uses for Paraplatin

Carboplatin and cisplatin appear to have similar efficacy in the treatment of platinum-responsive ovarian tumors,^{1 5 9 10 11 12 60 137 184 185} lung cancers†,^{18 29 121 137} and certain head and neck cancers†;^{17 137} carboplatin is less effective than cisplatin in certain testicular cancers.^{24 78 137 193}

Because carboplatin and cisplatin have different toxicity profiles,^{1 2 3 4 5 8 9 10 11 12 68} carboplatin may be effective in patients with platinum-responsive tumors who are unable to tolerate cisplatin because of renal impairment, refractory nausea, hearing impairment, or neuropathy;^{4 40 137} cisplatin may be preferred in patients with decreased bone marrow reserve or high risk of sepsis or those requiring anticoagulation therapy.^{10 137}

Ovarian Cancer

Treatment of ovarian cancer (alone and as combination therapy).^{1 9 29}

Combination therapy with platinum-containing agent (carboplatin or cisplatin) and paclitaxel† is the preferred regimen for initial treatment of advanced epithelial ovarian cancer; therapy with platinum-containing agent and paclitaxel is superior to therapy with platinum-containing agent and cyclophosphamide.^{9 29 60 137 139 147} Carboplatin is as effective as but less toxic than cisplatin when used in combination with paclitaxel^{184 185} or cyclophosphamide.^{10 11}

Carboplatin in combination with docetaxel has been used for the first-line treatment of ovarian cancer† and has demonstrated similar efficacy and a different tolerability profile (i.e., more hematologic toxicity but less neurotoxicity) compared with carboplatin in combination with paclitaxel.¹⁹⁶

Has been used as a single agent in the first-line treatment of advanced ovarian cancer†.^{9 29} Role remains to be established, but some clinicians consider single-agent carboplatin a reasonable option.^{29 137 187}

Used alone as second-line therapy for palliative treatment of recurrent ovarian cancer in patients with platinum-sensitive disease;^{1 2 9} nonplatinum-based regimens generally preferred for retreatment of patients with platinum-refractory disease.^{2 9 60 72}

Being studied for use in combination regimens for second-line treatment of advanced ovarian epithelial cancer†.^{9 188 189}

Has been used alone or in combination therapy for adjuvant treatment of early-stage ovarian cancer†.^{9 179 180} Survival benefit may be limited to patients whose disease is associated with poorer prognosis.^{137 179}

Lung Cancer

Treatment of small cell lung cancer† as a component of combination regimens.^{3 4 18 19 20 29 75 76}

An active agent in non-small cell lung cancer†.^{29 121 132 133 137 152 177 178 197 198}

Cervical Cancer

Role in the treatment of cervical cancer† remains to be established.^{157 166} Current evidence supports use of cisplatin in chemotherapy regimens given concurrently with radiation therapy in patients with locally advanced cervical cancer; similar benefit from carboplatin-containing chemotherapy cannot be assumed.^{157 166}

An active agent in the treatment of metastatic or recurrent cervical cancer†.^{29 163 164 165} May be considered an alternative to cisplatin, particularly in patients with nephrotoxicity or neurotoxicity caused by advanced cervical tumor who are not candidates for cisplatin therapy.^{163 164 165}

Head and Neck Cancer

May be useful in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck†.^{3 4 5 15 16 17 29 41 128 135 200}

Wilms’ Tumor

Has shown activity in the management of Wilms’ tumor†.^{29 65}

Brain Tumors

Has been used for palliative treatment of various primary brain tumors†.^{3 29}

Has shown activity in the treatment of progressive or recurrent low-grade gliomas in children†;^{29 56 57} responses observed in adults with recurrent glioma, including those who had received previous chemotherapy with nitrosoureas.^{29 170 171}

Has shown activity in the treatment of recurrent medulloblastoma†.^{56 130}

Combination therapy with platinum-containing agent (cisplatin or carboplatin) and etoposide is used for treatment of intracranial germ cell tumors†.^{29 169 176}

Neuroblastoma

Used (as combination therapy) fortreatment of neuroblastoma†.^{26 29}

Testicular Cancer

Cisplatin-based regimen (i.e., cisplatin/etoposide or cisplatin/etoposide/bleomycin) is more effective than carboplatin-based regimen (i.e., carboplatin/etoposide or carboplatin/etoposide/bleomycin) for initial treatment of good-prognosis metastatic nonseminomatous germ cell tumor; generally reserve use of carboplatin regimen for patients who do not tolerate or who refuse cisplatin.^{24 78 137 193}

Limited data suggest that high-dose carboplatin and etoposide may be effective in some patients with relapsed or refractory germ cell tumors†.^{23 30 59}

Bladder Cancer

Has been substituted as a less toxic alternative to cisplatin in the treatment of advanced bladder cancer† in some patients receiving combination chemotherapy.^{143 146}

Combination therapy with paclitaxel followed by carboplatin is being studied in patients with advanced bladder cancer, including those with abnormal renal function.^{97 131 168 190}

Retinoblastoma

Has been used in combination with etoposide in a limited number of children† with recurrent or progressive retinoblastoma†.^{102 106}

Breast Cancer

Has been used in a limited number of patients with metastatic breast cancer†.¹⁹⁹

Endometrial Cancer

Being studied in the treatment of advanced or recurrent endometrial cancer†.¹⁹⁵

Paraplatin Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

  
  


• 
  

  Carboplatin is considered a moderate antiemetic risk antineoplastic (i.e., 30–90% incidence of emesis without antiemetics).²⁰¹ Antiemetic therapy (e.g., a 5-HT₃ receptor antagonist and dexamethasone) is recommended to prevent nausea and vomiting.²⁰¹ (See Emetogenic Effects under Cautions.)

  
  


• 
  

  Pretreatment and posttreatment hydration and/or diuresis are not necessary.^{1 10 11 24 27 37} (See Renal Effects under Cautions.)

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion;¹ also has been administered intraperitoneally†.^{2 3 4 32 43 47}

Needles, syringes, catheters, and IV administration sets that contain aluminum parts which may come in contact with carboplatin should not be used for preparation or administration.¹

Reconstitution

Reconstitute vial containing 50, 150, or 450 mg of carboplatin powder for injection with 5, 15, or 45 mL, respectively, of sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection to provide a solution containing 10 mg/mL.^b

Resulting solutions can be further diluted to concentrations as low as 0.5 mg/mL with 5% dextrose injection or 0.9% sodium chloride injection.^b

Reconstituted solutions contain no preservatives; solutions preferably should be prepared immediately before use.^b

Dilution

May be diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration as low as 0.5 mg/mL.¹

Rate of Administration

Administer by IV infusion over a period of ≥15 minutes;^{1 2 4 10 13 25 27 42} also has been administered by continuous IV infusion over 24 hours.^{1 2 3}

Dosage

Base dosage on the clinical, renal, and hematologic response and tolerance of the patient in order to obtain optimum therapeutic response with minimum adverse effects.^{1 10 11}

Initial dosage can be based on body surface area, but dosage may be more accurately calculated using formula dosing methods based on the patient’s renal function.^{1 81 82 83 84 85 93 107 108 137} (See Methods for Individualization of Dosage under Dosage and Administration.)

When used as a component of a multiple-drug regimen, consult published protocols for the dosage of each chemotherapeutic agent and the method and sequence of administration.

Adults

Ovarian Cancer

Initial Therapy for Advanced (Stage III and IV) Ovarian Carcinoma

IV

Initially, 300 mg/m² given in combination with cyclophosphamide.^{1 10 11} Adjust subsequent dosage according to the patient’s hematologic tolerance of the previous dose (see Dosage Adjustment in the Treatment of Ovarian Cancer); do not administer doses until hematologic function is within acceptable limits.¹

Alternatively, calculate dosage using formula dosing methods (see Methods for Individualization of Dosage).^{1 81 82 83 84 85 93 107 108 137}

A course of carboplatin consists of single doses administered once every 4 weeks (or longer if delayed for hematologic toxicity) for a total of 6 cycles.^{1 10 11 69 70 71}

Secondary Treatment of Advanced Ovarian Cancer

IV

Initially, 360 mg/m² as monotherapy.¹ Administer drug once every 4 weeks (or longer if delayed for hematologic toxicity).¹ Adjust subsequent dosage according to the patient’s hematologic tolerance of the previous dose (see Dosage Adjustment in the Treatment of Ovarian Cancer); do not administer doses until hematologic function is within acceptable limits.^{1 137}

Dosage Adjustment in the Treatment of Ovarian Cancer

Dosage Adjustment Based on Hematologic Response to Previous Dose

Hematologic Toxicity	Recommended Dosage Adjustment
No hematologic toxicity (platelet count >100,000/mm3 and neutrophil count >2000/mm3)	Increase dosage by 25%1 10 11
Mild or moderate hematologic toxicity (platelet count 50,000–100,000/mm3 or neutrophil count 500–2000/mm3)	No adjustment in dosage1 10 11
Moderate to severe hematologic toxicity (platelet count <50,000/mm3 or neutrophil count <500/mm3)	Decrease dosage by 25%1 10 11 137

Other Malignant Neoplasms

IV

Consult published protocols for dosages and methods and sequences of administration. In general, escalation of dosages above 400 mg/m² results in substantial hematologic toxicity, but high-dose carboplatin (900–2000 mg/m²) has been used with colony-stimulating factors,^{40 67 121} autologous bone marrow rescue, and/or peripheral stem cell rescue.^{28 30 37 40 59 111 137}

Methods for Individualization of Dosage

Alternative methods for calculating initial carboplatin dosage have been suggested based on the patient’s pretreatment renal function or pretreatment renal function and desired platelet nadir.^{1 38 81 82 83 84 85 93 107 108}

Calvert Formula

Calculation is based on the patient’s GFR (in mL/minute) and the target AUC (in mg/mL per minute).^{1 81 82 83 93 137} Dosage is calculated in mg, not mg/m².¹

Calvert Formula for Carboplatin Dosing:
total dose (mg) = target AUC (in mg/mL per min) × [GFR (in mL/min) + 25]

A target AUC of 5 (range: 4–6) mg/mL per minute appears to provide the most appropriate dosage range for use of carboplatin alone in patients previously treated with chemotherapeutic agents.^{1 82 83 93}

Actual Toxicity in Previously Treated Patients1828393

AUC (mg/mL x min)	Percentage of Patients with Grade 3 or 4 Thrombocytopenia	Percentage of Patients with Grade 3 or 4 Leukopenia
4–5	16%	13%
6–7	33%	34%

For patients who previously did not receive chemotherapy, a target AUC of 7 (range: 6–8) mg/mL per minute has been recommended when carboplatin is used alone.^{82 83 93} Higher target AUCs (e.g., 7.5 mg/mL) also have been used (e.g., when carboplatin was used as a component of high-intensity dosing with paclitaxel and a hematopoietic agent for non-small cell lung carcinoma).¹²¹ Subsequent carboplatin dosage has been adjusted according to hematologic tolerance to the previous dose (e.g., reducing the dose by 25% for moderate to severe hematologic toxicity).¹²¹

Formula is not sufficiently accurate to determine dosage for children or for adults with severe renal impairment (i.e., GFR <20 mL/minute); therefore, do not use this formula in such patients.⁸³ Consult specialized references for an alternative pediatric formula.^{83 93 119 120}

Chatelut (French) Formula

Method does not require determination of GFR.^{84 85 93} Dosage is calculated in mg, not mg/m².^{84 93}

Chatelut (French) Formula for Carboplatin Dosing:
total dose (mg) = target AUC (in mg/mL per min) × carboplatin clearance (in mL/min)

When carboplatin clearance is calculated as follows:

Carboplatin Clearance:
Carboplatin clearance (mL/min) = (0.134 × wt) + ([218 × wt × (1 - {0.00457 × age})] × [1 - {0.314 × gender}] / serum creatinine (mcmol/L)) (where weight is in kg, age is in years, and gender is 0 for males and 1 for females)

Do not use this formula for calculating dosage in pediatric patients or those undergoing hemodialysis.⁸⁴

Special Populations

Renal Impairment

Reduce dosage in patients with Cl_cr <60 mL/minute.^{3 5 38}

Dosage Recommendations for Patients with Impaired Renal Function

Baseline Clcr	Initial Dose
41–59 mL/min	250 mg/m2
16–40 mL/min	200 mg/m2

Incidence of severe leukopenia, neutropenia, or thrombocytopenia at these adjusted initial dosages is about 25%.¹ Adjust subsequent dosage according to the patient’s hematologic tolerance to the previous dose.¹ Experience in patients with Cl_cr <15 mL/minute is too limited to make dosage recommendations.¹

Geriatric Patients

Use of dosing formulas incorporating estimates of GFR to determine dosage recommended in geriatric patients.¹

Cautions for Paraplatin

Contraindications

• 
  

  History of sensitivity reactions to carboplatin or other platinum-containing compounds (e.g., cisplatin).¹

  
  


• 
  

  Severe bone marrow depression or significant bleeding.¹

  
  

Warnings/Precautions

Warnings

Highly toxic drug with a low therapeutic index; therapeutic response is not likely to occur without some evidence of toxicity.^{1 10 11}

Hematologic Effects

The major and dose-limiting adverse effects are dose-related hematologic toxicity (thrombocytopenia, leukopenia, neutropenia, and/or anemia).^{1 2 3 4 5 10 11 27 28 53 56 66 67 79 80 93 121}

Myelosuppression appears to be most common and more severe in patients who received prior antineoplastic therapy (especially cisplatin-containing regimens), those concurrently receiving or having recently received other myelosuppressive drugs or radiation therapy, and those with renal impairment.^{1 3 38 53 66 67 82 83 84 85 93 101 121 137} Patients with poor performance status also appear to be at increased risk for severe leukopenia and thrombocytopenia.¹ (See Interactions.)

At usual dosages, thrombocytopenia is more common and pronounced than leukopenia.^{53 82 93} Thrombocytopenia may be cumulative and occasionally require transfusions.¹²¹ Potential for infection.^{1 10 11}

Anemia may be severe or symptomatic (e.g., accompanied by asthenia).^{1 10 11} Incidence appears to be cumulative.^{1 93 121} Transfusions may be required, particularly in patients receiving prolonged (>6 cycles) therapy.^{1 121 137}

Monitor hematologic status carefully; perform peripheral blood counts at frequent intervals.^{1 121}

Do not administer to patients with severe bone marrow depression or substantial bleeding.¹ In patients who experience myelosuppression, withhold subsequent cycles until neutrophil counts are >2000/mm³ and platelet counts are >100,000/mm³.¹

Treatment of severe hematologic toxicity may consist of supportive care, anti-infective agents for complicating infections, blood product transfusions, autologous bone marrow rescue, peripheral stem cell transplantation, and hematopoietic agents (colony-stimulating factors).^{1 30 40 93 121 137}

Emetogenic Effects

Carboplatin is classified as an antineoplastic agent of moderate emetic risk (i.e., 30–90% incidence of emesis without antiemetics).²⁰¹ Acute vomiting episodes are most common in patients who received prior emetogenic antineoplastic regimens (especially cisplatin-containing regimens) and in those receiving other emetogenic agents concurrently.^{1 201}

Possible reduction in the incidence of nausea and vomiting when given as a 24-hour continuous IV infusion or IV in divided doses over 5 consecutive days rather than as a single IV infusion; however, efficacy of these schedules not established.¹

Pretreatment with antiemetics may reduce incidence and severity of emesis; rarely, nausea and vomiting may be refractory to antiemetic therapy.^{1 3 93 103 136 201} For prevention of acute emesis, ASCO recommends a 2-drug antiemetic regimen consisting of a type 3 serotonin (5-HT₃) receptor antagonist and dexamethasone given before carboplatin.²⁰¹

For the prevention of delayed emesis following administration of carboplatin, ASCO recommends single-agent therapy with dexamethasone or a 5-HT₃ receptor antagonist.²⁰¹

Optimal use of antiemetics for prevention of acute and delayed emesis during early courses of therapy is the most important means for preventing anticipatory vomiting; behavioral modification, hypnosis, and drug therapy (e.g., benzodiazepine with or without conventional antiemetics) also may be useful.^{136 201}

Peripheral Neuropathies

Possible peripheral neuropathies, generally sensory (e.g., paresthesia).^{1 10 11 93} Increased incidence in patients >65 years of age,¹ those receiving prolonged therapy, and/or those who have received prior cisplatin therapy.^{1 93 121}

Preexisting cisplatin-induced peripheral neurotoxicity generally does not worsen during carboplatin therapy.¹

Otic Effects

Possible ototoxicity in patients receiving usual dosages of carboplatin in conjunction with cyclophosphamide.¹

Concomitant use of ototoxic drugs (e.g., aminoglycosides, furosemide, ifosfamide) may increase risk.^{93 111} (See Interactions.)

Ocular Effects

Loss of vision (sometimes complete for light and colors) reported in patients receiving higher than usually recommended dosages; improvement and/or total recovery of vision has occurred within weeks following drug discontinuance.^{1 31}

Hepatic Effects

Possible substantial abnormalities in liver function test results in patients receiving high doses (>4 times usual recommended dose) and autologous bone marrow transplantation.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; avoid pregnancy during therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Embryotoxic and teratogenic in rats.¹

Sensitivity Reactions

Hypersensitivity Reactions

Prior exposure to other platinum-containing agents increases the risk for carboplatin-induced allergic reactions, including anaphylaxis.¹

Exposure (e.g., industrial) to platinum-containing compounds can cause asthma and immediate and delayed hypersensitivity reactions;^{33 36 93} consider the possibility that patients with a history of such exposure may be cross-sensitive to carboplatin.³⁶

Observe closely for possible hypersensitivity reactions.^{1 61} Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of such reactions (e.g., antihistamines, epinephrine, oxygen, corticosteroids) should be readily available when carboplatin is administered.^{1 61}

General Precautions

Mutagenicity and Carcinogenicity

Mutagenic in vitro and in vivo.¹

Carcinogenic potential not fully studied; however, drugs with similar mechanisms of action and evidence of mutagenic effects have been reported to be carcinogenic.¹ Secondary malignancies reported in patients receiving carboplatin in combination with other agents.¹

Renal Effects

Nephrotoxicity is less common and severe than that associated with cisplatin; concomitant IV hydration and diuresis generally not necessary.^{1 10 11 24 27 37 92 93} However, consider the possibility that nephrotoxicity may be potentiated by other nephrotoxic drugs.¹ (See Interactions.)

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether carboplatin or its platinum-containing products are distributed into milk.¹ Discontinue nursing during therapy.¹

Pediatric Use

Safety and efficacy not established.¹

Limited experience in the treatment of germ cell tumors in adolescents ≥16 years of age,²⁴ various brain tumors or neuroblastoma in children 6 months to 19 years of age,^{26 27 28 56 62} and Wilms’ tumor in children 2–15 years of age.^{66 79 80}

Adverse effects reported to date in children are similar to those reported in adults and include hematologic toxicity (principally thrombocytopenia),^{27 28 56 66 79 80} adverse GI effects (e.g., nausea, vomiting),^{27 28 56 66} hypersensitivity reactions (e.g., urticaria, facial swelling, abdominal pain, coryza, cough),⁶² and hearing loss (particularly at higher than recommended doses in combination with other ototoxic agents).¹

Geriatric Use

In clinical trials evaluating carboplatin as combination therapy for ovarian cancer, age was not found to be a factor for survival in patients ≥65 years of age relative to younger adults.¹

Possible increased incidence of severe thrombocytopenia and carboplatin-induced peripheral neuropathy in adults ≥65 years of age compared with younger patients.¹

Consider increased incidence of decreased renal function in geriatric population (see Geriatric Patients under Dosage and Administration).¹³⁷

Renal Impairment

Increased risk of severe bone marrow depression in patients with renal impairment; monitor renal function carefully.^{1 40 82 83 84 85 93} Cl_cr appears to most accurately reflect kidney function in patients receiving carboplatin.^{1 40 82 83 84 85 93}

Reduce dosage in patients with renal impairment.^{3 5 38} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Thrombocytopenia,¹ neutropenia,¹ leukopenia,¹ anemia,¹ nausea,^{1 201} vomiting,^{1 201} electrolyte abnormalities (hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia),¹ alkaline phosphatase elevations.¹

Interactions for Paraplatin

Ototoxic Drugs

Hearing loss reported in children receiving carboplatin at higher than recommended doses in combination with other ototoxic drugs.¹

Nephrotoxic Drugs

Possible potentiation of renal effects.¹

Emetogenic Drugs

Concomitant use with emetogenic drugs or use in individuals who previously received emetogenic therapy is associated with an increased incidence of emesis.^{1 201}

Specific Drugs and Therapies

Drug or Therapy	Interaction	Comments
Aminoglycosides	Increased risk of nephrotoxicity and/or ototoxicity1	Use with caution1
Antineoplastic agents	Prior antineoplastic therapy may increase risk of bone marrow suppression1
Myelosuppressive agents	Possible potentiation of hematologic toxicity1 3 66 67 101	Monitor carefully; manage dosage and time of administration to minimize additive toxic effects1 93 137
Radiation therapy	Possible potentiation of hematologic toxicity1 3 66 67 101	Monitor carefully; manage dosage and time of administration to minimize additive toxic effects1 93 137

Paraplatin Pharmacokinetics

Complex pharmacokinetics involve the parent compound as well as total platinum (protein-bound and nonprotein-bound platinum) and ultrafilterable platinum (carboplatin and nonprotein-bound carboplatin metabolites).^{1 2 3 4 43 44}

Absorption

Bioavailability

Following IV infusion, peak plasma concentrations of carboplatin, total platinum, and ultrafilterable platinum occur immediately.^{3 42 44 46}

Following intraperitoneal administration†, peak plasma concentrations of total platinum, free platinum, and carboplatin are attained within 2–4 hours following instillation.^{3 4 43 47}

Distribution

Extent

Widely distributed into body tissues and fluids, with highest concentrations in the kidney, liver, skin, and tumor tissue;^{3 43 44} lower concentrations found in fat and brain.^{3 43} Also distributed into erythrocytes.^{43 44}

Not known whether carboplatin or its platinum-containing products cross the placenta or are distributed into milk.¹

Plasma Protein Binding

Carboplatin is not bound to plasma proteins, but degrades to platinum-containing products which rapidly bind to protein.^{45 49}

<24% of platinum is bound to plasma proteins during the first 4 hours after IV administration of carboplatin; within 24 hours, 87% is protein bound.⁴⁶

Elimination

Metabolism

Metabolic fate has not been completely elucidated.^{1 3 4 5 6 7 43} No evidence to date that the drug undergoes enzymatic biotransformation; the bidentate dicarboxylate ligands of carboplatin are believed to be displaced by water, forming positively charged platinum complexes that react with nucleophilic sites on DNA.^{1 3 4 5 6 7 43}

Elimination Route

Carboplatin and its platinum-containing product(s) are excreted principally in urine (predominantly via glomerular filtration).^{1 3 4 43 44}

Carboplatin (as ultrafilterable carboplatin) is removed extensively by hemodialysis.^{54 86}

Half-life

Plasma elimination half-lives (t_½β) for carboplatin and ultrafilterable platinum: 2–3 hours.^{1 43 44}

Terminal elimination half-life (t_½γ) for total platinum: 4–6 days.^{43 44}

Special Populations

In patients with impaired renal function, renal clearance and total body clearance of platinum are reduced.^{3 4 38 54} In patients undergoing hemodialysis, t_½β values for total and ultrafilterable platinum are increased compared with values in individuals with normal renal function.^{43 54}

Stability

Storage

Parenteral

Injection Concentrate

25°C (may be exposed to 15–30°C).¹ Protect from light.¹

Discard unused solution 14 days after initial entry into vial.¹

Discard diluted solutions 8 hours after preparation.¹

Powder for Injection

20–25°C; protect from light.^b

Reconstituted solutions are stable for 8 hours at room temperature (25°C).^b Reconstituted solutions contain no preservatives; discard after 8 hours.^b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^a

Compatible
Dextrose 5% in sodium chloride 0.2, 0.45, or 0.9%
Dextrose 5% in water
Sodium chloride 0.9%
Incompatible

Promethazine with DM

Generic Name: dextromethorphan and promethazine (dex troe me THOR fan and pro METH a zeen)

Brand Names: Promethazine with Dextromethorphan, Promethazine with DM

What is Promethazine with DM (dextromethorphan and promethazine)?

Dextromethorphan is a cough suppressant. It affects the signals in the brain that trigger cough reflex.

Promethazine is an antihistamine. It blocks the effects of the naturally occurring chemical histamine in your body.

The combination of dextromethorphan and promethazine used to treat cough, itching, runny nose, sneezing, and itchy or watery eyes caused by colds or allergies.

Dextromethorphan will not treat a cough that is caused by smoking, asthma, or emphysema.

Dextromethorphan and promethazine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about dextromethorphan?

Call your doctor immediately if you experience uncontrollable movements of your eyes, lips, tongue, face, arms, or legs. These could be early signs of dangerous side effects. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not use dextromethorphan and promethazine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take dextromethorphan and promethazine before the MAO inhibitor has cleared from your body. Do not use any other over-the-counter cough, cold, or allergy medication without first asking your doctor or pharmacist. If you take certain products together you may accidentally take too much of one or more types of medicine. Read the label of any other medicine you are using to see if it contains dextromethorphan. Dextromethorphan will not treat a cough that is caused by smoking, asthma, or emphysema.

What should I discuss with my healthcare provider before taking Promethazine with DM (dextromethorphan and promethazine)?

Do not use dextromethorphan and promethazine if you have asthma or other lung disease. Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take a cough or cold medicine before the MAO inhibitor has cleared from your body.

Before taking dextromethorphan and promethazine, tell your doctor if you are allergic to any drugs, or if you have emphysema or chronic bronchitis. You may not be able to use this medication, or you may need a dosage adjustment or special tests during treatment.

Before taking dextromethorphan and promethazine, tell your doctor if you have:

• 
  

  epilepsy or another seizure disorder;

  
  


• 
  

  emphysema or chronic bronchitis;

  
  


• 
  

  sleep apnea (breathing stops during sleep);

  
  


• 
  

  glaucoma;

  
  


• 
  

  a stomach ulcer or digestive obstruction;

  
  


• 
  

  bone marrow disorder;

  
  


• 
  

  problems with urination;

  
  


• 
  

  high blood pressure or heart disease; or

  
  


• liver disease.

If you have any of these conditions, you may not be able to use dextromethorphan and promethazine, or you may need a dosage adjustment or special tests during treatment.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether this medication passes into breast milk or if it could harm an unborn baby. Do not use dextromethorphan and promethazine without telling your doctor if you are breast-feeding a baby.

How should I take Promethazine with DM (dextromethorphan and promethazine)?

Take this medication exactly as it has been prescribed by your doctor. Do not use the medication in larger amounts, or use it for longer than recommended. Follow the directions on your prescription label. Cough or cold medicine is usually taken only for a short time until your symptoms clear up.

Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children.

Measure the liquid form of this medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash.

If you need to have any type of surgery, tell the surgeon ahead of time if you have taken a cough medicine within the past few days.

Store dextromethorphan and promethazine at room temperature, away from heat, light, and moisture.

What happens if I miss a dose?

Since cough and cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Symptoms of a dextromethorphan and promethazine overdose may include feeling restless or nervous, severe drowsiness, dizziness, dry mouth, large pupils, flushing, nausea, vomiting, shallow breathing, and fainting.

What should I avoid while taking Promethazine with DM (dextromethorphan and promethazine)?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of dextromethorphan and promethazine.

Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with cough medicine can increase your risk of unpleasant side effects.

Avoid using other drugs that make you sleepy (such as cold medicine, sleeping pills, pain medication, muscle relaxers, and medicine for seizures, depression or anxiety).

Do not use any other over-the-counter cough, cold, or allergy medication without first asking your doctor or pharmacist. Dextromethorphan is contained in many medicines available over the counter. If you take certain products together you may accidentally take too much of this medicine. Read the label of any other medicine you are using to see if it contains dextromethorphan.

Promethazine with DM (dextromethorphan and promethazine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using dextromethorphan and promethazine and call your doctor at once if you have any of these serious side effects:

• 
  

  uncontrollable movements of your eyes, lips, tongue, face, arms, or legs;

  
  


• 
  

  tremors, twitching, or uncontrolled muscle movements in your face, arms, or legs.

  
  


• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  hallucinations (seeing or hearing things);

  
  


• 
  

  confusion, hallucinations; or

  
  


• 
  

  slow, shallow breathing, weak pulse;

  
  


• 
  

  nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

  
  


• 
  

  fever, muscle stiffness, confusion, fast or uneven heartbeat, sweating, fainting.

  
  

Keep taking dextromethorphan and promethazine and talk with your doctor if you have any of these less serious side effects:

• 
  

  dizziness, drowsiness, sleepiness, or confusion;

  
  


• 
  

  blurred vision, dry mouth;

  
  


• 
  

  ringing in your ears;

  
  


• 
  

  nausea or vomiting; or

  
  


• 
  

  increased sensitivity to sunlight.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Promethazine with DM (dextromethorphan and promethazine)?

Before taking dextromethorphan and promethazine, tell your doctor if you are using any of the following drugs:

• 
  

  celecoxib (Celebrex);

  
  


• 
  

  cinacalcet (Sensipar);

  
  


• 
  

  darifenacin (Enablex);

  
  


• 
  

  imatinib (Gleevec);

  
  


• 
  

  quinidine (Quinaglute, Quinidex);

  
  


• 
  

  ranolazine (Ranexa)

  
  


• 
  

  ritonavir (Norvir);

  
  


• 
  

  sibutramine (Meridia);

  
  


• 
  

  terbinafine (Lamisil);

  
  


• 
  

  medicines to treat high blood pressure;

  
  


• 
  

  antidepressant medications such as amitriptyline (Elavil, Etrafon), bupropion (Wellbutrin, Zyban), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Janimine, Tofranil), paroxetine (Paxil), sertraline (Zoloft), and others.

  
  


• 
  

  sedatives or anxiety medicines such as alprazolam (Xanax), diazepam (Valium), chlordiazepoxide (Librium), temazepam (Restoril), or triazolam (Halcion);

  
  


• 
  

  phenobarbital (Luminal), amobarbital (Amytal) and secobarbital (Seconal); or

  
  


• 
  

  atropine (Donnatal, and others), belladonna, clidinium (Quarzan), dicyclomine (Bentyl), glycopyrrolate (Robinul), hyoscyamine (Anaspaz, Cystospaz, Levsin, and others), methscopolamine (Pamine), and scopolamine (Transderm-Scop).

  
  

If you are using any of these drugs, you may not be able to use dextromethorphan and promethazine, or you may need dosage adjustments or special tests during treatment.

There may be other drugs not listed that can affect dextromethorphan and promethazine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Promethazine with DM resources

• Promethazine with DM Side Effects (in more detail)
• Promethazine with DM Use in Pregnancy & Breastfeeding
• Promethazine with DM Drug Interactions
• Promethazine with DM Support Group
• 0 Reviews for Promethazine with DM - Add your own review/rating

• Promethazine DM Prescribing Information (FDA)

Compare Promethazine with DM with other medications

• Cold Symptoms
• Cough
• Hay Fever

Where can I get more information?

• Your pharmacist has information about dextromethorphan and promethazine written for health professionals that you may read.

See also: Promethazine with DM side effects (in more detail)

Humulin R U-500

Dosage Form: injection, solution
INFORMATION FOR THE PHYSICIAN

HUMULIN® R

REGULAR

U-500 (CONCENTRATED)

INSULIN HUMAN INJECTION, USP

(rDNA ORIGIN)

DESCRIPTION

Humulin R® U-500 is a polypeptide hormone structurally identical to human insulin synthesized through rDNA technology in a special non-disease-producing laboratory strain of Escherichia coli bacteria. Humulin R U-500 has the empirical formula C257H383N65O77S6 and a molecular weight of 5808.

Humulin R U-500 is a sterile, clear, aqueous and colorless solution that contains human insulin (rDNA origin) 500 units/mL, glycerin 16 mg/mL, metacresol 2.5 mg/mL and zinc oxide to supplement the endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and water for injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

Humulin R U-500 is for subcutaneous injection only. It should not be used intravenously or intramuscularly. Humulin R U-500 contains 500 units of insulin in each milliliter (5-times more concentrated than Humulin R U-100 [see DOSAGE AND ADMINISTRATION]). It also contains 16 mg glycerin, 2.5 mg metacresol as a preservative, and zinc-oxide calculated to supplement endogenous zinc to obtain a total zinc content of 0.017 mg/100 units and water for injection. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

Adequate insulin dosage permits patients with diabetes to effectively utilize carbohydrates, proteins and fats. Regardless of dose strength, insulin enables carbohydrate metabolism to occur and thus to prevent the production of ketone bodies by the liver. Some patients might develop severe insulin resistance such that daily doses of several hundred units of insulin or more are required.

CLINICAL PHARMACOLOGY

Regulation of glucose metabolism is the primary activity of insulin. Insulin lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis, proteolysis, and gluconeogenesis, and enhance protein synthesis and conversion of excess glucose into fat.

Administered insulin, including Humulin R U-500, substitutes for inadequate endogenous insulin secretion and partially corrects the disordered metabolism and inappropriate hyperglycemia of diabetes mellitus, which are caused by either a deficiency or a reduction in the biologic effectiveness of insulin. When administered in appropriate doses at prescribed intervals to patients with diabetes mellitus, Humulin R U-500 restores their ability to metabolize carbohydrates, proteins and fats.

As with all insulin preparations, the duration of action of Humulin R U-500 is dependent on dose, site of injection, blood supply, temperature, and physical activity.

Humulin R U-500 is unmodified by any agent that might prolong its action. Clinical experience has shown that it frequently has time action characteristics reflecting both prandial and basal activity. It takes effect within 30 minutes, has a peak similar to that observed with U-100 regular human insulin and has a relatively long duration of activity following a single dose (up to 24 hours) as compared with U-100 regular insulins. This effect has been credited to the high concentration of the preparation. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual.

Indications and Usage for Humulin R U-500

Humulin R U-500 is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 1 and type 2 diabetes mellitus.

Humulin R U-500 is useful for the treatment of insulin-resistant patients with diabetes requiring daily doses of more than 200 units, since a large dose may be administered subcutaneously in a reasonable volume.

Contraindications

Humulin R U-500 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humulin R U-500 or any of its excipients.

Warnings

Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, etc.), species, or method of administration may result in the need for a change in dosage.

Humulin R U-500 contains 500 units of insulin in each milliliter (5-times more concentrated than Humulin R U-100). For Humulin R U-500, extreme caution must be observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia.

Precautions

Dosing Confusion/Dosing Errors

Medication errors associated with Humulin R U-500 have occurred and resulted in patients experiencing hyperglycemia, hypoglycemia or death. The majority of errors occurred due to errors in dispensing, prescribing or administration. Attention to the following details may prevent:

• Dispensing errors

The Humulin R U-500 vial, which contains 20 mL, versus the Humulin R U-100 vial, which contains 10 mL – is marked with a band of diagonal brown stripes to distinguish it from the U-100 vial, which has no stripes. “U-500” is also highlighted in red on the label.

• Prescribing errors (see DOSAGE AND ADMINISTRATION)

The prescribed dose of Humulin R U-500 should always be expressed in actual units of Humulin R U-500 along with corresponding markings on the syringe the patient is using (i.e., a U-100 insulin syringe or tuberculin syringe [see DOSAGE AND ADMINISTRATION]).

• Administration errors (see DOSAGE AND ADMINISTRATION)

A majority of these errors occurred due to dosing confusion when the Humulin R U-500 dose was prescribed in units or volume corresponding to a U-100 syringe or tuberculin syringe markings, respectively, or the prescribed dose was administered without recognizing that the markings on the syringe used do not directly correspond to U-500 dose. Instructions for use should always be read and followed before use.

Instruct the patient to inform hospital or emergency department staff of the dose of Humulin R U-500 prescribed, in the event of a future hospitalization or visit to the Emergency Department.

A conversion chart is provided and should always be used when administering Humulin R U-500 doses with U-100 insulin syringes or tuberculin syringes.

Hypoglycemia

Hypoglycemia is the most common adverse reaction of all insulin therapies, including Humulin R U-500. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with Humulin R U-500.

As with all insulin preparations, the time course of Humulin R U-500 action may vary in different individuals or at different times in the same individual and is dependent on dose, site of injection, blood supply, temperature, and physical activity.

Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stresses. Concomitant oral antidiabetic treatment may need to be adjusted.

Any patient who requires Humulin R U-500 for control of diabetes should be under close observation until appropriate dosage is established. The response will vary among patients. Most patients will require 2 or 3 injections per day.

Insulin resistance, in some patients is transitory; after several weeks or months during which high dosage is required, responsiveness to the pharmacologic effect of insulin may be regained and dosage can be reduced.

The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia (see PRECAUTIONS, Drug Interactions).

As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may prevent a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Severe hypoglycemia may develop 18 to 24 hours after the original injection of Humulin R U-500.

Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Non-Ketotic Syndrome

Hyperglycemia, diabetic ketoacidosis, or hyperosmolar coma may develop if the patient takes less Humulin R U-500 than needed to control blood glucose levels. This could be due to increases in insulin demand during illness or infection, neglect of diet, omission or improper administration of prescribed insulin doses or use of drugs that affect glucose metabolism or insulin sensitivity. Early signs of diabetic ketoacidosis include glycosuria and ketonuria. Polydipsia, polyuria, loss of appetite, fatigue, dry skin, abdominal pain, nausea and vomiting and compensatory tachypnea come on gradually, usually over a period of some hours or days, in conjunction with hyperglycemia and ketonemia. Severe sustained hyperglycemia may result in hyperosmolar coma or death.

Hypokalemia

Insulin stimulates potassium movement into the cells, possibly leading to hypokalemia, that left untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Humulin R U-500 (see ADVERSE REACTIONS).

Localized reactions and generalized myalgias have been reported with the use of metacresol as an injectable excipient.

Renal or Hepatic Impairment

Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment.

Drug Interactions

Some medications may alter insulin requirements and the risk for hypoglycemia and hyperglycemia (see ADVERSE REACTIONS, Drug Interactions).

Use in Pregnancy

Pregnancy Category B — All pregnancies have background risk of birth defects, miscarriage, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and is decreased with good glucose control. It is important for patients to maintain good control of diabetes before conception and during pregnancy. Special attention should be paid to diet, exercise and insulin regimens. Insulin requirements may decrease during the first trimester, usually increase during the second and third trimesters and rapidly decline after delivery. Careful glucose monitoring is essential in these patients. Female patients should be advised to tell their physician if they intend to become, or if they become pregnant.

Studies show that endogenous insulin only crosses the placenta in minimal amounts. While there are no adequate and well-controlled studies in pregnant women, an extensive body of published literature demonstrates the maternal and fetal benefits of insulin treatment in patients with diabetes during pregnancy. Humulin R U-500 is a recombinant human insulin that is identical to the endogenous hormone; therefore, reproduction and fertility studies were not performed in animals.

Labor and Delivery

Careful glucose monitoring and management of patients with diabetes during labor and delivery are required.

Nursing Mothers

Endogenous insulin is present in human milk. Insulin orally ingested is degraded in the gastrointestinal tract. In lactating infants, no adverse reactions have been associated with maternal use of insulin. In a study of eight preterm infants between 26 to 30 weeks gestation, enteral administration of Humulin R did not result in hypoglycemia. Good glucose control supports lactation in patients with diabetes. Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.

Pediatric Use

There are no well-controlled studies of use of Humulin R U-500 in children.

Adverse Reactions

Hypoglycemia

Hypoglycemia is one of the most frequent adverse events experienced by insulin users.

Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:

sweating	drowsiness
dizziness	sleep disturbances
palpitation	anxiety
tremor	blurred vision
hunger	slurred speech
restlessness	depressed mood
tingling in the hands, feet, lips, or tongue	irritability
lightheadedness	abnormal behavior
inability to concentrate	unsteady movement
headache	personality changes

Signs of severe hypoglycemia can include:

disorientation	seizures
unconsciousness	coma
death

Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, autonomic diabetic neuropathy, use of medications such as beta-adrenergic blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes.

Without recognition of early warning symptoms, the patient may not be able to take steps to avoid more serious hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose more frequently, especially prior to activities such as driving. Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy, non-diet carbohydrate-containing drinks or glucose tablets.

Hypoglycemia when using Humulin R U-500 can be prolonged and severe.

Hypokalemia

See Precautions

Lipodystrophy

Administration of insulin subcutaneously can result in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue).

Allergy

Local Allergy — Patients occasionally experience erythema, local edema, and pruritus at the site of injection. This condition usually is self-limiting. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.

Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy (anaphylaxis) may be life threatening.

Weight gain

Weight gain can occur with some insulin therapies and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.

Peripheral Edema

Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Drug Interactions

The concurrent use of oral antihyperglycemic diabetes agents with Humulin R U-500 is not recommended since there are limited data to support such use.

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

Drugs that may increase the blood-glucose-lowering effect of Humulin R U-500 and susceptibility to hypoglycemia:

• Oral antihyperglycemic diabetes agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors [SSRIs]), pramlintide, disopyramide, fibrates, fluoxetine, propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (e.g., octreotide), and alcohol.

Drugs that may reduce the blood-glucose-lowering effect:

• Corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents, somatropin, atypical antipsychotics, glucagon, protease inhibitors and thyroid replacement therapy.

Drugs that may increase or decrease blood-glucose-lowering effect:

• Beta-adrenergic blockers, clonidine, lithium salts, and alcohol.


• Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Drugs that may mask the signs of hypoglycemia:

• Beta-adrenergic blockers, clonidine, guanethidine, and reserpine.

OVERDOSAGE

Excess insulin may cause hypoglycemia and hypokalemia. Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

Humulin R U-500 Dosage and Administration

Humulin R U-500 is usually given two or three times daily before meals. The dosage and time of Humulin R U-500 should be individualized and determined, based on the physician's advice, in accordance with the needs of the patient. The injection of Humulin R U-500 should be followed by a meal within approximately 30 minutes of administration.

The average range of total daily insulin requirement for maintenance therapy in insulin-treated patients without severe insulin resistance lies between 0.5 and 1.0 unit/kg/day. However, in pre-pubertal children it usually varies from 0.7 to 1.0 unit/kg/day, but can be much lower during the period of partial remission. In situations of insulin resistance, e.g., during puberty or due to obesity, the daily insulin requirement may be substantially higher. Initial dosages for type 2 diabetes patients are often lower, e.g., 0.2 to 0.4 units/kg/day.

Humulin R U-500 is useful for the treatment of insulin resistant patients with diabetes requiring daily doses of more than 200 units, since a large dose may be administered subcutaneously in a reasonable volume.

Humulin R U-500 may be administered by subcutaneous injection in the abdominal wall, the thigh, the gluteal region or in the upper arm. Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites. Injection into a lifted skin fold minimizes the risk of intramuscular injection. Injection sites should be rotated within the same region. As with all insulin, the duration of action will vary according to the dose, injection site, blood flow, temperature, and level of physical activity.

Humulin R U-500 should only be administered subcutaneously. Do not administer Humulin R U-500 intravenously or intramuscularly.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Never use Humulin R U-500 if it has become viscous (thickened) or cloudy; use it only if it is clear and colorless. Humulin R U-500 should not be used after the printed expiration date.

Do not mix Humulin R U-500 with other insulins, as there are no data to support such use.

When administering Humulin R U-500

If U-100 insulin syringes are used, since their markings are in units and are designed and intended for use with the less concentrated U-100 insulin products, it is extremely important to explain the amount of Humulin R U-500 insulin to be administered in both actual dose and with specification of “unit markings” on the U-100 syringe.

If tuberculin syringes are used, since their markings are in volume (mL), the actual amount of Humulin R U-500 should be explained in both actual dose and with specification of volume (mL). Table 1 contains conversion information using both U-100 insulin and tuberculin syringes to help avoid dose confusion.

Table 1: Conversion Information for Humulin R U-500 Insulin Dose When Using a U-100 Insulin Syringe or a Tuberculin Syringe

Humulin R U-500 dose (units)	U-100 insulin syringe (unit markings)	Tuberculin syringe (volume in mL)
25	5	0.05
50	10	0.1
75	15	0.15
100	20	0.2
125	25	0.25
150	30	0.3
175	35	0.35
200	40	0.4
225	45	0.45
250	50	0.5
275	55	0.55
300	60	0.6
325	65	0.65
350	70	0.7
375	75	0.75
400	80	0.8
425	85	0.85
450	90	0.9
475	95	0.95
500	100	1.0
Dose (actual Humulin R U-500 units)	Divide dose (actual Humulin R U-500 units) by 5	Divide dose (actual Humulin R U-500 units) by 500

For doses other than those listed above refer to the following formulas:

U-100 insulin syringe

Divide prescribed Dose (actual units) by 5 = Unit markings in a U-100 insulin syringe.

Tuberculin syringe

Divide prescribed Dose (actual units) by 500 = Volume (mL) in a tuberculin syringe

Storage

Not in-use (unopened): Humulin R U-500 vials not in-use should be stored in a refrigerator, (2° to 8°C [36° to 46°F]), but not in the freezer.

In-use (opened): The Humulin R U-500 vial currently in-use can be kept unrefrigerated as long as it is kept as cool as possible (below 30°C [86°F]) away from heat and light. In-use vials must be used within 31 days or be discarded, even if they still contain Humulin R U-500.

Do not use Humulin R U-500 after the expiration date stamped on the label or if it has been frozen.

How is Humulin R U-500 Supplied

 Vials, 500 units/mL, 20 mL (HI-500) (1s),      NDC 0002-8501-01

Literature revised March 21, 2011

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

Copyright © 1996, 2011, Eli Lilly and Company. All rights reserved.

PA 3054 AMP

PATIENT INFORMATION

Humulin®(HU-mu-lin) R

Regular

U-500 (Concentrated)

insulin human injection, USP (rDNA origin)

Read the Patient Information that comes with Humulin® R U-500 before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your diabetes or treatment.

What is the most important information I should know about Humulin R U-500?

Humulin R U-500 (500 units/mL) contains 5 times as much insulin in 1 mL as standard U-100 (100 units/mL) insulin. This means that it is more concentrated than standard U-100 insulin.

Know your insulin. Make sure you know the strength, dose and type of insulin that is prescribed for you. Do not change the strength, dose or type of insulin you use unless told to do so by your healthcare provider.

It is important that you take the right dose of Humulin R U-500. Taking too much Humulin R U-500 can cause life-threatening low blood sugar (hypoglycemia) or death. Taking too little Humulin R U-500 can cause high blood sugar (hyperglycemia).

There are no special syringes to measure Humulin R U-500. It is important that you use only the syringes that your healthcare provider tells you to use. Your healthcare provider should tell you how much Humulin R U-500 to take and when to take it. Your healthcare provider should show you how to draw up Humulin R U-500. The amount of Humulin R U-500 will be less than the amount of standard U-100 insulin which would be drawn up into the syringe. See the section, “How should I take Humulin R U-500?”

What is Humulin R U-500?

Humulin R U-500 is a prescription medicine used to treat high blood sugar in people with diabetes mellitus. Humulin R U-500 is a man-made insulin that is similar to the insulin produced by the human pancreas. Humulin R U-500 is used along with diet and exercise to lower blood sugar in people with:

• type 1 diabetes.


• type 2 diabetes whose blood sugars are not controlled well with diabetes medicine taken by mouth.

Humulin R U-500 is useful for the treatment of insulin-resistant patients with diabetes who need more than 200 units of insulin a day.

It is not known if Humulin R U-500 is safe and effective in children.

Who should not take Humulin R U-500?

Do not take Humulin R U-500 if:

• your blood sugar is too low (hypoglycemia). See the section, “What are the possible side effects of Humulin R U-500?” for more information on low blood sugar.


• you are allergic to any of the ingredients in Humulin R U-500. See the end of this leaflet for a complete list of ingredients in Humulin R U-500.

What should I tell my healthcare provider before taking Humulin R U-500?

Before you take Humulin R U-500, tell your healthcare provider if you:

• have liver or kidney problems or any other medical conditions. Certain medical conditions can affect your insulin needs and your dose of Humulin R U-500.


• are pregnant, plan to become pregnant, or are breast-feeding. It is not known if Humulin R U-500 will harm your unborn baby or breast-feeding child. You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant or breast-feeding. It is especially important to keep good control of your blood sugar during pregnancy.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Many medicines can affect your blood sugar levels and your insulin needs. Your Humulin R U-500 dose may need to change if you take other medicines. Especially tell your healthcare provider if you take other medicines to treat your diabetes.

Know the medicines you take. Keep a list of your medicines with you and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take Humulin R U-500?

• Take Humulin R U-500 exactly as prescribed.


• Do not make any changes to your strength, dose or type of insulin unless you are told to do so by your healthcare provider.


• Check the label carefully to make sure you have the right type and strength of insulin prescribed for you.


• Your healthcare provider should show you how to prepare and inject Humulin R U-500 before you start taking it.


• Humulin R U-500 should look clear and colorless. Do not use Humulin R U-500 if it does not look clear, colorless or has particles in it. Talk with your pharmacist or healthcare provider if you have any questions.


• Follow your healthcare provider's instructions about how often you should check your blood sugar level for hypoglycemia (too low blood sugar) and hyperglycemia (too high blood sugar).


• Humulin R U-500 starts working about 30 minutes after injection. The effects of Humulin R U-500 may last up to 24 hours.


• You should eat a meal within 30 minutes of injecting Humulin R U-500.


• Choose an injection area (upper arm, abdomen, buttocks, or thigh). Change injection sites within the area you choose for each dose. Do not inject into the exact same spot for each injection. Never inject Humulin R U-500 into a vein or muscle.


• Inject Humulin R U-500 under your skin (subcutaneous), as shown to you by your healthcare provider.


• Your healthcare provider should regularly check your diabetes with blood tests, including your blood sugar levels and hemoglobin A1C.


• If you take too much Humulin R U-500, your blood sugar may fall too low (hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking or eating something sugary right away. Always carry a quick source of sugar, such as hard candy, fruit juice or glucose tablets.


• Your healthcare provider may prescribe a glucagon emergency kit so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth.

There are no special syringes to measure Humulin R U-500. It is important that you use only the syringes that your healthcare provider tells you to use to give your injections of Humulin R U-500. You should use either a U-100 insulin syringe or tuberculin syringe as instructed by your healthcare provider.

• If you are using U-100 insulin syringes, your healthcare provider should explain how to use this syringe to give the prescribed dose with the unit markings on the syringe.


• If you are using tuberculin syringes, your healthcare provider should explain how to use this syringe to give the prescribed dose with volume markings on the syringe.

If you do not use the right syringe type, you may take the wrong dose of Humulin R U-500. This can cause you to have too low blood sugar (hypoglycemia) or too high blood sugar (hyperglycemia).

Make sure you know:

• your prescribed dose of Humulin R U-500.


• which syringe to use and how to draw up your prescribed dose.

If you do not understand your dose, talk with your healthcare provider about how much insulin to take.

If you are hospitalized or go to an emergency room, make sure to tell the hospital staff the actual dose of Humulin R U-500 that your healthcare provider has prescribed for you.

Your healthcare provider may change your dose of Humulin R U-500 because of:

• illness


• change in diet


• stress


• change in physical activity or exercise


• other medicines you take


• travel

Check your blood sugar and stay on the diet and exercise plan as prescribed by your healthcare provider.

• Do not share needles or syringes with others.


• Place used needles and syringes in a closable, puncture-resistant container. You may use a sharps container (such as a red biohazard container) or a hard plastic container (such as a detergent bottle) or a metal container (such as an empty coffee can). Ask your healthcare provider for instructions on the right way to throw away the container. There may be state and local laws about how you should throw away used needles and syringes.


• Do not throw the container in household trash and do not recycle.

What should I avoid while taking Humulin R U-500?

• Alcohol. Drinking alcohol may affect your blood sugar when you take Humulin R U-500.


• Driving and operating machinery. You may have trouble paying attention or reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a car or operate machinery. Ask your healthcare provider if it is all right for you to drive if you have:
  
  • Low blood sugar (hypoglycemia)
  
  
  • Decreased or no warning signs of low blood sugar
  
  

What are the possible side effects of Humulin R U-500?

Humulin R U-500 can cause serious side effects, including:

• See the section “What is the most important information I should know about Humulin R U-500?”


• Low blood sugar (hypoglycemia).

Symptoms of low blood sugar may happen suddenly with Humulin R U-500. Symptoms of mild or moderate low blood sugar may include:

sweating	drowsiness
dizziness	trouble sleeping
fast heart beat	feeling anxious
tremor	blurred vision
hunger	slurred speech
restlessness	depressed mood
tingling in the hands, feet, lips or tongue	feeling irritable
lightheadedness	abnormal behavior
trouble concentrating	walking unsteady
headache	personality changes

Humulin R U-500 can cause low blood sugar (hypoglycemia) that is severe and that can last a long time.

• Severe low blood sugar can cause you to become confused, pass out (become unconscious), have seizures or coma, and could cause death.

Talk to your healthcare provider about how to tell if you have low blood sugar and what to do if this happens while taking Humulin R U-500. Know your symptoms of low blood sugar. Follow your healthcare provider's instructions for treating your low blood sugar.

Tell your healthcare provider if low blood sugar is a problem for you. Your healthcare provider may need to change the amount of Humulin R U-500 that you take, change your meal plans or your exercise program to help you avoid low blood sugar.

• Serious allergic reactions. Get medical help right away if you have any of these symptoms of a severe allergic reaction:
  
  • rash all over your body
  
  
  • shortness of breath
  
  
  • trouble breathing (wheezing)
  
  
  • fast heart beat
  
  
  • sweating
  
  
  • feel faint
  
  
  • Low potassium (hypokalemia) in your blood. Your healthcare provider may do blood tests to check you for low potassium.
  
  

Common side effects of Humulin R U-500 include:

• Skin thickening or pits at the injection site (lipodystrophy). Change (rotate) where you inject your insulin to help prevent these skin changes from happening. Do not inject insulin into this type of skin. Do not inject into the exact same spot for each injection.


• Injection site reactions (local allergic reaction). Symptoms may include: redness, swelling and itching at the injection site. Tell your healthcare provider if you have skin reactions that do not go away.


• Weight gain


• Swelling due to fluid retention

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effect of Humulin R U-500. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Humulin R U-500?

Unopened vials of Humulin R U-500:

• Keep unopened vials of Humulin R U-500 in a refrigerator at 36°F to 46°F (2°C to 8°C).


• Do not freeze. Do not use Humulin R U-500 if it has been frozen.


• Do not use Humulin R U-500 after the expiration date stamped on the label.

Opened (in-use) vial of Humulin R U-500:

• Keep opened vial of Humulin R U-500 in the refrigerator or at room temperature below 86°F (30°C).


• Keep Humulin R U-500 away from heat and direct sunlight.


• The opened vial must be used within 31 days of opening. Throw away any opened vial after 31 days of use, even if there is insulin left in the vial.


• Do not use Humulin R U-500 after the expiration date stamped on the label.

Keep Humulin R U-500 and all medicines out of the reach of children.

General Information about Humulin R U-500

Medicines are sometimes prescribed for purposes other than those listed in patient information leaflets. Do not use Humulin R U-500 for a condition for which it was not prescribed. Do not give Humulin R U-500 to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Humulin R U-500. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Humulin R U-500 that is written for healthcare professionals.

For more information about Humulin R U-500 call 1-800-545-5979 or go to www.lilly.com.

What are the ingredients in Humulin R U-500?

Active ingredient: human insulin rDNA origin

Inactive ingredients: glycerin, metacresol, zinc oxide, water for injection, sodium hydroxide or hydrochloric acid.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Patient Information revised May 20, 2011

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

PA 8901 AMP

PACKAGE CARTON – Humulin R U-500 Vial 20 mL 1ct

Rx only

NDC 0002-8501-01

20 mL

HI-500

U-500

(Concentrated)

Humulin® R

REGULAR

insulin human injection, USP (rDNA origin)

500 units per mL

IMPORTANT:

SEE INSTRUCTIONS FOR USE.

www.lilly.com

Lilly

HUMULIN  R U-500 insulin human  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0002-8501 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Insulin human (Insulin human) Insulin human 500 [iU]  in 1 mL

Inactive Ingredients Ingredient Name Strength Glycerin 16 mg  in 1 mL Metacresol 2.5 mg  in 1 mL Zinc 0.085 mg  in 1 mL Water   Hydrochloric acid   Sodium hydroxide

Product Characteristics Color