Elleste Duet 1mg & 2mg

Elleste Duet 1mg and 2mg

(estradiol and norethisterone acetate)

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, please ask your doctor or 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 Elleste Duet is and what it is used for


• 2. Before you take Elleste Duet


• 3. How to take Elleste Duet


• 4. Possible side effects


• 5. How to store Elleste Duet


• 6. Further information

What Elleste Duet Is And What It Is Used For

Elleste Duet is a form of hormone replacement therapy (HRT).

It contains two hormones, estradiol hemihydrate and norethisterone acetate. Elleste Duet is one of a group of medicines called combined estrogen-progestogen preparations. It is not an oral contraceptive.

Why has your doctor given you Elleste Duet?

Elleste Duet treats the symptoms of the menopause (change of life).

As you approach the menopause, your ovaries gradually produce fewer hormones. This may cause unpleasant symptoms such as hot flushes and sweating. Elleste Duet replaces hormones which you lose during the menopause, and prevents or relieves any unpleasant symptoms. Your doctor will aim to give you the lowest dose required to treat your symptoms.

Other changes in your bones may take place over a longer time. These changes can lead to an increased risk of your bones breaking or cracking. If you are at an increased risk of fractures due to osteoporosis (thinning of the bones) but are unable to take other treatments or if other therapies prove to be ineffective, Elleste Duet 2mg may also be used for this purpose. Your doctor should discuss all the available options with you.

Before You Take Elleste Duet

Elleste Duet may not be suitable for all women. Read the list below.

DO NOT take Elleste Duet, if you have, or have ever had:

• a blood clot in a vein in your leg or anywhere else (a "deep vein thrombosis");


• a blood clot that has travelled to your lung or another part of the body (an "embolus");


• narrowed or blocked arteries possibly leading to angina and heart disease;


• breast or womb cancer;


• unexplained vaginal bleeding;


• liver problems, for example, jaundice (yellowing of the skin or eyes);


• porphyria (a rare inherited blood disease);


• untreated endometrial hyperplasia (an overgrowth of the lining of your womb).

Also do not take Elleste Duet if you:

• are pregnant or think you could be pregnant;


• are breast-feeding; or


• have ever had an allergic reaction to any of the ingredients in Elleste Duet (see Section 6).

Safety of HRT

As well as benefits, HRT has some risks which you need to consider when you're deciding whether to take it, or whether to carry on taking it.

Take special care with Elleste Duet

Before you start taking HRT, your doctor should ask about your own and your family's medical history. Your doctor may decide to examine your breasts and/or your abdomen, and may do an internal examination - but only if these examinations are necessary for you, or if you have any special concerns.

Certain diseases sometimes get worse when you are taking hormone replacement therapy. Your doctor may need to check you more closely if you have any of the following:

• Migraine or severe headache


• Asthma


• Gallstones


• Epilepsy


• High blood pressure


• A personal or family history of blood clots


• Diabetes (see below)


• Liver problems


• Heart or kidney problems


• Endometrial hyperplasia (overgrowth of the lining of your womb)


• Fibroids in your womb (see below)


• Endometriosis (where tissue from your womb is found outside the womb)


• A history of breast cancer in your family


• Systemic lupus erythematosus (SLE; a chronic inflammatory disease affecting the skin and organs)


• Otosclerosis (an inherited form of deafness which sometimes gets worse during pregnancy)


• High levels of lipids in your blood (hypertriglyceridaemia)

Elleste Duet may affect the results of certain laboratory tests, so tell the person taking the sample that you are taking Elleste Duet.

If you have fibroids (lumps of fibrous and muscular tissue) in your womb, these may increase in size when you are taking Elleste Duet. See your doctor if you have any pain or swelling in your abdomen.

If you are a diabetic, you may need to change the amount of insulin you take. Check your blood glucose level more often until it is steady.

Do I need to use contraception while I am taking Elleste Duet?

It is important to remember that Elleste Duet is not an oral contraceptive (the pill).

If you are using the pill or another hormonal contraceptive you will need to use another type of contraceptive. Please discuss this with your doctor.

Once you've started on HRT, you should:

• see your doctor for regular check-ups (at least once a year).
  
  At these check-ups, your doctor may discuss with you the benefits and risks of continuing to take HRT.


• 
  go for regular breast screening and cervical smear tests


• 
  regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel.

Effects on your heart or circulation

Heart disease:

HRT is not recommended for women who have heart disease, or have had heart disease recently. If you have ever had heart disease, talk to your doctor to see if you should be taking HRT.

HRT will not help to prevent heart disease.

Studies with one type of HRT (containing conjugated estrogen plus the progestogen MPA) have shown that women may be slightly more likely to get heart disease during the first year of taking the medication. For other types of HRT, the risk is likely to be similar, although this is not yet certain.

If you get:

• a pain in your chest that spreads to your arm or neck

See a doctor as soon as possible and do not take any more HRT until your doctor says you can. This pain could be a sign of heart disease.

Stroke:

Recent research suggests that HRT slightly increases the risk of having a stroke.

Other things that can increase the risk of stroke include:

• getting older


• high blood pressure


• smoking


• drinking too much alcohol


• an irregular heartbeat

If you are worried about any of these things, or if you have had a stroke in the past, talk to your doctor to see if you should take HRT.

Compare

Looking at women in their 50s who are not taking HRT - on average, over a 5-year period, 3 in 1000 would be expected to have a stroke. For women in their 50s who are taking HRT, the figure would be 4 in 1000.

Looking at women in their 60s who are not taking HRT - on average, over a 5-year period, 11 in 1000 would be expected to have a stroke.

For women in their 60s who are taking HRT, the figure would be 15 in 1000.

If you get:

• unexplained migraine-type headaches, with or without disturbed vision

See a doctor as soon as possible and do not take any more HRT until your doctor says you can. These headaches may be an early warning sign of a stroke.

Blood clots:

HRT may increase the risk of blood clots in the veins (also called deep vein thrombosis, or DVT), especially during the first year of taking it. These blood clots are not always serious, but if one travels to the lungs, it can cause chest pain, breathlessness, collapse or even death. This condition is called pulmonary embolism, or PE.

DVT and PE are examples of a condition called venous thromboembolism, or VTE.

You are more likely to get a blood clot if you:

• are seriously overweight


• have had a blood clot before or have a close family member who has had blood clots


• have had one or more miscarriages


• have any blood clotting problem that needs treatment with a medicine such as warfarin


• are off your feet for a long time because of major surgery, injury or illness


• have a rare condition called systemic lupus erythematosus (SLE).

If any of these apply to you, talk to your doctor to see if you should take HRT.

Compare

Looking at women in their 50s who are not taking HRT - on average, over a 5-year period, 3 in 1000 would be expected to get a blood clot.

For women in their 50s who are taking HRT, the figure would be 7 in 1000.

Looking at women in their 60s who are not taking HRT - on average, over a 5-year period, 8 in 1000 would be expected to get a blood clot.

For women in their 60s who are taking HRT, the figure would be 17 in 1000.

The following may be signs of a blood clot if you get:

• painful swelling in your leg


• sudden chest pain


• difficulty breathing

See a doctor as soon as possible and do not take any more HRT until your doctor says you can.

If you're going to have surgery, make sure your doctor knows about it. You may need to stop taking HRT about 4 to 6 weeks before the operation, to reduce the risk of a blood clot. Your doctor will tell you when you can start taking HRT again.

Effects on your risk of developing cancer

Breast cancer:

Women who have breast cancer, or have had breast cancer in the past, should not take HRT.

Taking HRT slightly increases the risk of breast cancer; as does having a later menopause. Your risk of breast cancer is also higher if you:

• have a close relative (mother, sister or grandmother) who has had breast cancer


• are seriously overweight.

The risk for a post-menopausal woman taking estrogen-only HRT for 5 years is about the same as for a woman of the same age who is still having periods over that time and not taking HRT. The risk for a woman who is taking estrogen plus progestogen HRT is higher than for estrogen-only HRT (but estrogen plus progestogen HRT is beneficial for the endometrium, see 'Endometrial cancer' below).

For all kinds of HRT, the extra risk of breast cancer increases the longer you take it, but returns to normal within about 5 years after stopping.

Compare

Looking at women aged 50 who are not taking HRT - on average, 32 in 1000 will be diagnosed with breast cancer by the time they reach the age of 65.

For women who start taking estrogen-only HRT at age 50 and take it for 5 years, the figure will be between 33 and 34 in 1000 (ie an extra 1-2 cases).

If they take estrogen-only HRT for 10 years, the figure will be 37 in 1000 (ie an extra 5 cases).

For women who start taking estrogen plus progestogen HRT at age 50 and take it for 5 years, the figure will be 38 in 1000 (ie an extra 6 cases).

If they take estrogen plus progestogen HRT for 10 years, the figure will be 51 in 1000 (ie an extra 19 cases).

If you notice any changes in your breasts, such as:

• dimpling of the skin


• changes in the nipple


• any lumps you can see or feel

Make an appointment to see your doctor as soon as possible.

Endometrial cancer (cancer of the lining of the womb):

Taking estrogen-only HRT for a long time can increase the risk of cancer of the lining of the womb (the endometrium). Taking a progestogen as well as the estrogen helps to lower the extra risk. Elleste Duet also contain progestogen.

If you still have your womb, your doctor may prescribe a progestogen as well as estrogen. If so, these may be prescribed separately, or as a combined HRT product.

If you have had your womb removed (a hysterectomy), your doctor will discuss with you whether you can safely take estrogen without a progestogen.

If you've had your womb removed because of endometriosis, any endometrium left in your body may be at risk. So your doctor may prescribe HRT that includes a progestogen as well as an estrogen.

Compare

Looking at women who still have a uterus and who are not taking HRT - on average 5 in 1000 will be diagnosed with endometrial cancer between the ages of 50-65.

For women who take estrogen-only HRT, the figure will be between 10 and 60 in 1000 (ie an extra 5 to 55 cases), depending on the dose and how long you take it.

The addition of a progestogen to estrogen-only HRT substantially reduces the risk of endometrial cancer.

If you get breakthrough bleeding or spotting, it's usually nothing to worry about, especially during the first few months of taking HRT. But if the bleeding or spotting:

• carries on for more than the first few months


• starts after you've been on HRT for a while


• carries on even after you've stopped taking HRT

Make an appointment to see your doctor. It could be a sign that your endometrium has become thicker.

Ovarian cancer:

Ovarian cancer (cancer of the ovaries) is very rare, but it is serious. It can be difficult to diagnose, because there are often no obvious signs of the disease.

Some studies have indicated that taking estrogen-only HRT for more than 5 years may increase the risk of ovarian cancer. It is not yet known whether other kinds of HRT increase the risk in the same way.

Taking other medicines with Elleste Duet

Please tell your doctor or pharmacist if you are using or have recently used any other medicines, including over-the-counter medicines.

In particular, tell your doctor if you are using any of the following because they may alter the effects of Elleste Duet:

• drugs that treat epilepsy, and some anti-infectives (anti-virals or antibiotics) and sedatives.


• herbal medicines containing St. John's Wort.

If your doctor does not know that you are taking these other medicines, tell him or her before you start taking Elleste Duet.

Elleste Duet may affect your blood glucose level. If you are being treated for diabetes please let your doctor or pharmacist know that you take Elleste Duet.

Pregnancy and breast-feeding

Elleste Duet is for use in post-menopausal women. It should not be taken by pregnant or breast-feeding women.

Driving or using machines

No effects on driving or using machinery have been observed for Elleste Duet.

Important information about some of the ingredients of Elleste Duet

Elleste Duet contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Sunset yellow colouring in Elleste Duet 2mg can cause allergic-type reactions, including asthma. This allergy is more common in people who are allergic to aspirin.

How To Take Elleste Duet

The Elleste Duet 1mg pack contains 16 white tablets and 12 pale green tablets.

• You must start with the white tablets.

The Elleste Duet 2mg pack contains 16 orange tablets and 12 grey tablets.

• You must start with the orange tablets.

If you are still having regular periods, start on the first day of bleeding.

If you are not having regular periods you can start straight away.

• Take one tablet each day. You can take the tablet at a time of the day that suits you but it is best to take it at about the same time each day.


• Swallow the tablets whole, with some water.


• Follow the direction of the arrows on the pack and take a tablet each day until the pack is empty.


• When you finish your first foil strip, start a new strip on the next day.
  
  Remember to put a fresh sticker on your new foil strip.

To help you remember to take your tablets, we have included stickers in the pack with the days of the week marked on them. For example, if you are starting the tablets on a Friday, use the sticker which starts with 'Fri'. Stick this at the top of the foil strip on the side where you can see the tablets.

If you are taking

• Elleste Duet 1mg, the first day should be above the white tablet which has the start arrow next to it.


• Elleste Duet 2mg, the first day should be above the orange tablet which has the start arrow next to it.

Changing from another type of HRT

If you are changing from another type of HRT, start taking Elleste Duet when you finish the pack of HRT you are taking at the moment.

If your doctor gives you instructions on changing from another type of HRT you should follow these instructions. If you have any doubts you should contact your doctor.

Will I have periods?

You will probably have a monthly bleed. This may start any time between day 21 of the pack to day 5 of the next pack. This pattern will usually be the same from month to month. Some women may have no bleeds.

In the first few months you may get irregular bleeding. However, if this carries on you should tell your doctor.

If you forget to take a tablet

Take the tablet as soon as you remember, and take the next one at the normal time.

If you have missed your tablet by more than 12 hours, dispose of this tablet safely and take the next one at the normal time. You may experience some breakthrough bleeding or spotting.

If you take more than you should

There should be no problems, but you may feel sick or actually be sick. If you are worried, contact your doctor. Take the usual tablet the following day.

Possible Side Effects

Like all medicines, Elleste Duet can cause side effects, although not everybody gets them. 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.

Stop taking the tablets immediately and tell your doctor if:

• you become jaundiced (yellowing of the skin or eyes);


• you have itching all over your body;


• you have an unusual, severe or prolonged headache;


• your sight is affected in any way;


• you find it difficult to speak;


• any part of your body suddenly feels weak or numb;


• there is a chance that you could be or could become pregnant; or


• you develop any of the conditions listed under "Before you take Elleste Duet".

During the first few months you may feel sick, have headaches, or your breasts may be painful or increase in size. These side effects should lessen as your body gets used to the medicine.

You may also get the following side effects:

Common: feeling sick, stomach cramps, headache, an increase in size of fibroids in the womb, breakthrough bleeding, changes in weight, oedema (swelling) of legs, breast tenderness and enlargement, mood changes, changes in sex drive.

Uncommon: indigestion, being sick, flatulence, gallstones and gallbladder disease, feeling dizzy, migraine, vaginal thrush, increase in blood pressure, leg cramps, breast cancer (please refer to the earlier section on breast cancer).

Rare: loss of hair from the scalp, increase in body and facial hair, itchiness, rashes, thromboembolic disease (please refer to the earlier section on the effects of HRT on the heart and circulation).

Very rare: heart disease (please refer to the earlier section on the effects of HRT on the heart and circulation), stroke, chloasma (brown patches on the skin), red swellings on the skin.

HRT will not prevent memory loss. In one study of women who started using combined HRT after the age of 65, a small increase in the risk of dementia was observed.

How To Store Elleste Duet

Keep out of the reach and sight of children.

Do not store Elleste Duet 1mg above 30°C.

Do not store Elleste Duet 2mg above 25°C.

Store in the original package.

Do not take Elleste Duet after the 'expiry date' shown on the box.

If your tablets are out of date, take them to your pharmacist who will dispose of them safely.

Further Information

What Elleste Duet contains

Each strip of Elleste Duet 1mg contains the active ingredients:

• 16 white tablets containing 1 milligram estradiol (as hemihydrate)


• 12 pale green tablets containing 1 milligram estradiol (as hemihydrate) and 1 milligram norethisterone acetate.

Each strip of Elleste Duet 2mg contains the active ingredients:

• 16 orange tablets containing 2 milligrams estradiol (as hemihydrate)


• 12 grey tablets containing 2 milligrams estradiol (as hemihydrate) and 1 milligram norethisterone acetate

(The estradiol hemihydrate used to make Elleste Duet does not come from animals).

The tablets also contain: lactose monohydrate, maize starch, povidone, talc, magnesium stearate, macrogol 400 and hypromellose (E464).

• Elleste Duet 1mg contains the colours indigo carmine (E132), quinoline yellow (E104) and titanium dioxide (E171).


• Elleste Duet 2mg contains the colours sunset yellow (E110), titanium dioxide (E171) and black iron oxide (E172). (see also the warning at the end of section 2)

What Elleste Duet looks like and contents of the pack

One pack of Elleste Duet 1mg tablets contains white and pale green film-coated tablets with an embossing.

One pack of Elleste Duet 2mg tablets contains orange and grey film-coated tablets with an embossing.

They are supplied in three blister strips in each pack. Each strip contains 28 tablets.

Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

Manufacturer

Piramal Healthcare UK Ltd.

Whalton Road

Morpeth

Northumberland

NE61 3YA

UK

This leaflet was last approved in October 2009.

If you have any comments on the way this leaflet is written, please write to Medical Information at

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

5014/PIL9

5027/PIL9

20701186

Navelbine Injection

vinorelbine tartrate

Dosage Form: injection
NAVELBINE® (vinorelbine tartrate) Injection

Warning

NAVELBINE (vinorelbine tartrate) Injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. This product is for intravenous (IV) use only. Intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing this product should be labeled "WARNING - FOR IV USE ONLY. FATAL if given intrathecally."

Severe granulocytopenia resulting in increased susceptibility to infection may occur. Granulocyte counts should be ≥1,000 cells/mm3 prior to the administration of NAVELBINE. The dosage should be adjusted according to complete blood counts with differentials obtained on the day of treatment.

Caution - It is extremely important that the intravenous needle or catheter be properly positioned before NAVELBINE is injected. Administration of NAVELBINE may result in extravasation causing local tissue necrosis and/or thrombophlebitis (see DOSAGE AND ADMINISTRATION: Administration Precautions).

Navelbine Injection Description

NAVELBINE (vinorelbine tartrate) Injection is for intravenous administration. Each vial contains vinorelbine tartrate equivalent to 10 mg (1-mL vial) or 50 mg (5-mL vial) in Water for Injection. No preservatives or other additives are present. The aqueous solution is sterile and nonpyrogenic. Vinorelbine tartrate is a semi-synthetic vinca alkaloid with antitumor activity.

The chemical name is 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2, 3-dihydroxybutanedioate (1:2)(salt)].

Vinorelbine tartrate has the following structure:

vinorelbine tartrate is a white to yellow or light brown amorphous powder with the molecular formula C45H54N4O8•2C4H6O6 and molecular weight of 1079.12. The aqueous solubility is >1,000 mg/mL in distilled water. The pH of Navelbine Injection is approximately 3.5.

Navelbine Injection - Clinical Pharmacology

Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. In intact tectal plates from mouse embryos, vinorelbine, vincristine and vinblastine inhibited mitotic microtubule formation at the same concentration (2 µM), inducing a blockade of cells at metaphase. Vincristine produced depolymerization of axonal microtubules at 5 µM, but vinblastine and vinorelbine did not have this effect until concentrations of 30 µM and 40 µM, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.

Pharmacokinetics

The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 in 4 clinical trials. Doses were administered by 15- to 20-minute constant-rate infusions. Following intravenous administration, vinorelbine concentration in plasma decays in a triphasic manner. The initial rapid decline primarily represents distribution of drug to peripheral compartments followed by metabolism and excretion of the drug during subsequent phases. The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. The terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma clearance ranges from 0.97 to 1.26 L/hr/kg. Steady-state volume of distribution (VSS) values range from 25.4 to 40.1 L/kg.

Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in pooled human plasma over a concentration range of 234 to 1,169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin.

Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine. Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes (see PRECAUTIONS).

The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed, but based on experience with other anticancer vinca alkaloids, dose adjustments are recommended for patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION).

The disposition of radiolabeled vinorelbine given intravenously was studied in a limited number of patients. Approximately 18% and 46% of the administered dose was recovered in the urine and in the feces, respectively. Incomplete recovery in humans is consistent with results in animals where recovery is incomplete, even after prolonged sampling times.

A separate study of the urinary excretion of vinorelbine using specific chromatographic analytical methodology showed that 10.9% ± 0.7% of a 30-mg/m2 intravenous dose was excreted unchanged in the urine.

The influence of age on the pharmacokinetics of vinorelbine was examined using data from 44 cancer patients (average age, 56.7 ± 7.8 years; range, 41 to 74 years; with 12 patients ≥60 years and 6 patients ≥65 years) in 3 studies. CL (the mean plasma clearance), t1/2 (the terminal phase half-life), and Vz (the volume of distribution during terminal phase) were independent of age. A separate pharmacokinetic study was conducted in 10 elderly patients with metastatic breast cancer (age range, 66 to 81 years; 3 patients >75 years; normal liver function tests) receiving vinorelbine 30 mg/m2 intravenously. CL, Vss, and t1/2 were similar to those reported for younger adult patients in previous studies. No relationship between age, systemic exposure (AUC0-∞), and hematological toxicity was observed.

The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin with NAVELBINE (see PRECAUTIONS: Drug Interactions).

Clinical Trials

Data from 1 randomized clinical study (211 evaluable patients) with single-agent NAVELBINE and 2 randomized clinical trials (1,044 patients) using NAVELBINE combined with cisplatin support the use of NAVELBINE in patients with advanced non-small cell lung cancer (NSCLC).

Single-Agent NAVELBINE

Single-agent NAVELBINE was studied in a North American, randomized clinical trial in which patients with Stage IV NSCLC, no prior chemotherapy, and Karnofsky Performance Status ≥70 were treated with NAVELBINE (30 mg/m2) weekly or 5-fluorouracil (5-FU) (425 mg/m2 IV bolus) plus leucovorin (LV) 20 mg/m2 IV bolus) daily for 5 days every 4 weeks. A total of 211 patients were randomized at a 2:1 ratio to NAVELBINE (143) or 5-FU/LV (68). NAVELBINE showed improved survival time compared to 5-FU/LV.

In an intent-to-treat analysis, the median survival time was 30 weeks versus 22 weeks for patients receiving NAVELBINE versus 5-FU/LV, respectively (P=0.06). The 1-year survival rates were 24% (±4% SE) for NAVELBINE and 16% (±5% SE) for the 5-FU/LV group, using the Kaplan-Meier product-limit estimates. The median survival time with 5-FU/LV was similar to or slightly better than that usually observed in untreated patients with advanced NSCLC, suggesting that the difference was not related to some unknown detrimental effect of 5-FU/LV therapy. The response rates (all partial responses) for NAVELBINE and 5-FU/LV were 12% and 3%, respectively.

NAVELBINE in Combination with Cisplatin: NAVELBINE plus Cisplatin versus Single-Agent Cisplatin

A Phase III open-label, randomized study was conducted which compared NAVELBINE (25 mg/m2/week) plus cisplatin (100 mg/m2 every 4 weeks) to single-agent cisplatin (100 mg/m2 every 4 weeks) in patients with Stage IV or Stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe who were not previously treated with chemotherapy. Patients included in the study had a performance status of 0 or 1, and 34% had received prior surgery and/or radiotherapy. Characteristics of the 432 randomized patients are provided in Table 1. Two hundred and twelve patients received NAVELBINE plus cisplatin and 210 received single-agent cisplatin. The primary objective of this trial was to compare survival between the 2 treatment groups. Survival (Figure 1) for patients receiving NAVELBINE plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized in Table 1

NAVELBINE plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent NAVELBINE

In a large European clinical trial, 612 patients with Stage III or IV NSCLC, no prior chemotherapy, and WHO Performance Status of 0, 1, or 2 were randomized to treatment with single-agent NAVELBINE (30 mg/m2/week), NAVELBINE (30 mg/m2/week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2/week for 7 weeks, then every other week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks). Patient characteristics are provided in Table 1. Survival was longer in patients treated with NAVELBINE plus cisplatin compared to those treated with vindesine plus cisplatin (Figure 2). Study results are summarized in Table 1.

Dose-Ranging Study

A dose-ranging study of NAVELBINE (20, 25, or 30 mg/m2/week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks) in 32 patients with NSCLC demonstrated a median survival of 10.2 months. There were no responses at the lowest dose level; the response rate was 33% in the 21 patients treated at the 2 highest dose levels.

Table 1: Randomized Clinical Trials of NAVELBINE in Combination with Cisplatin in NSCLC

	NAVELBINE Cisplatin vs. Single-Agent Cisplatin		NAVELBINE/Cisplatin vs. Vindesine/Cisplatin vs. Single-Agent NAVELBINE
	NAVELBINE/ Cisplatin	Cisplatin	NAVELBINE/ Cisplatin	Vindesine/ Cisplatin	NAVELBINE
Demographics    Number of patients    Number of males    Number of females	214 146 68	218 141 77	206 182 24	200 179 21	206 188 18
Median age (years) Range (years)	63 33-84	64 37-81	59 32-75	59 31-75	60 30-74
Stage of disease    Stage IIIA    Stage IIIB    Stage IV    Local recurrence    Metastatic after surgery	NA 8% 92% NA NA	NA 8% 92% NA NA	11% 28% 50% 2% 9%	11% 25% 55% 3% 8%	10% 32% 47% 3 % 9 %
Histology    Adenocarcinoma    Squamous    Large cell    Unspecified	54% 19% 14% 13%	52% 22% 14 % 13%	32% 56% 13% NA	40% 50% 11% NA	28% 56% 16% NA
Results    Median survival (months)	7.8	6.2	9.2*†	7.4	7.2
P value	P = 0.01		*P = 0.09 vs. vindesine/cisplatin † = 0.05 vs. single-agent NAVELBINE
12-Month survival rate	38%	22%	35%	27%	30%
Overall response	19%	8%	28%‡§	19%	14%
P value	P<0.001		‡P = 0.03 vs. vindesine/cisplatin §P<0.001 vs. single-agent NAVELBINE

Indications and Usage for Navelbine Injection

NAVELBINE is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced non-small cell lung cancer (NSCLC). In patients with Stage IV NSCLC, NAVELBINE is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, NAVELBINE is indicated in combination with cisplatin

Contraindications

Administration of NAVELBINE is contraindicated in patients with pretreatment granulocyte counts <1,000 cells/mm3 (see WARNINGS).

Warnings

NAVELBINE should be administered in carefully adjusted doses by or under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Patients treated with NAVELBINE should be frequently monitored for myelosuppression both during and after therapy. Granulocytopenia is dose-limiting. Granulocyte nadirs occur between 7 and 10 days after dosing with granulocyte count recovery usually within the following 7 to 14 days. Complete blood counts with differentials should be performed and results reviewed prior to administering each dose of NAVELBINE. NAVELBINE should not be administered to patients with granulocyte counts <1,000 cells/mm3. Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/or fever. See DOSAGE AND ADMINISTRATION for recommended dose adjustments for granulocytopenia. Acute shortness of breath and severe bronchospasm have been reported infrequently, following the administration of NAVELBINE and other vinca alkaloids, most commonly when the vinca alkaloid was used in combination with mitomycin. These adverse events may require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly when there is pre-existing pulmonary dysfunction. Reported cases of interstitial pulmonary changes and acute respiratory distress syndrome (ARDS), most of which were fatal, occurred in patients treated with single-agent NAVELBINE. The mean time to onset of these symptoms after vinorelbine administration was 1 week (range 3 to 8 days). Patients with alterations in their baseline pulmonary symptoms or with new onset of dyspnea, cough, hypoxia, or other symptoms should be evaluated promptly.

NAVELBINE has been reported to cause severe constipation (e.g., Grade 3-4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation. Some events have been fatal.

Pregnancy

Pregnancy Category D. NAVELBINE may cause fetal harm if administered to a pregnant woman. A single dose of vinorelbine has been shown to be embryo- and/or fetotoxic in mice and rabbits at doses of 9 mg/m2 and 5.5 mg/m2, respectively (one third and one sixth the human dose). At nonmaternotoxic doses, fetal weight was reduced and ossification was delayed. There are no studies in pregnant women. If NAVELBINE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with NAVELBINE.

Precautions

General

Most drug-related adverse events of NAVELBINE are reversible. If severe adverse events occur, NAVELBINE should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with NAVELBINE should be carried out with caution and alertness as to possible recurrence of toxicity. NAVELBINE should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from the effects of previous chemotherapy (see DOSAGE AND ADMINISTRATION). Administration of NAVELBINE to patients with prior radiation therapy may result in radiation recall reactions (see ADVERSE REACTIONS and Drug Interactions). Patients with a prior history or pre-existing neuropathy, regardless of etiology, should be monitored for new or worsening signs and symptoms of neuropathy while receiving NAVELBINE.

Care must be taken to avoid contamination of the eye with concentrations of NAVELBINE used clinically. Severe irritation of the eye has been reported with accidental exposure to another vinca alkaloid. If exposure occurs, the eye should immediately be thoroughly flushed with water.

Information for Patients

Patients should be informed that the major acute toxicities of NAVELBINE are related to bone marrow toxicity, specifically granulocytopenia with increased susceptibility to infection. They should be advised to report fever or chills immediately. Women of childbearing potential should be advised to avoid becoming pregnant during treatment. Patients should be advised to contact their physician it they experience increased shortness of breath, cough, or other new pulmonary symptoms, or if they experience symptoms of abdominal pain or constipation.

Laboratory Tests

Since dose-limiting clinical toxicity is the result of depression of the white blood cell count, it is imperative that complete blood counts with differentials be obtained and reviewed on the day of treatment prior to each dose of NAVELBINE (see ADVERSE REACTIONS: Hematologic).

Hepatic

There is no evidence that the toxicity of NAVELBINE is enhanced in patients with elevated liver enzymes. No data are available for patients with severe baseline cholestasis, but the liver plays an important role in the metabolism of NAVELBINE. Because clinical experience in patients with severe liver disease is limited, caution should be exercised when administering NAVELBINE to patients with severe hepatic injury or impairment (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Acute pulmonary reactions have been reported with NAVELBINE and other anticancer vinca alkaloids used in conjunction with mitomycin. Although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of granulocytopenia with NAVELBINE used in combination with cisplatin is significantly higher than with single-agent NAVELBINE. Patients who receive NAVELBINE and paclitaxel, either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy. Administration of NAVELBINE to patients with prior or concomitant radiation therapy may result in radio sensitizing effects. Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinorelbine tartrate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of NAVELBINE has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouse lymphoma TK Locus assay. The significance of these or other short-term test results for human risk is unknown. Vinorelbine did not affect fertility to a statistically significant extent when administered to rats on either a once-weekly (9 mg/m2, approximately one third the human dose) or alternate-day schedule (4.2 mg/m2, approximately one seventh the human dose) prior to and during mating. However, biweekly administration for 13 or 26 weeks in the rat at 2.1 and 7.2 mg/m2 (approximately one fifteenth and one fourth the human dose) resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

Pregnancy

Pregnancy Category D. See WARNINGS section.

Nursing Mothers

It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from NAVELBINE, it is recommended that nursing be discontinued in women who are receiving therapy with NAVELBINE.

Pediatric Use

Safety and effectiveness of NAVELBINE in pediatric patients have not been established. Data from a single-arm study in 46 patients with recurrent solid malignant tumors, including rhabdomyosarcoma/undifferentiated sarcoma, neuroblastoma, and CNS tumors, at doses similar to those used in adults, showed no meaningful clinical activity. Toxicities were similar to those reported in adults.

Geriatric Use

Of the total number of patients in North American clinical studies of IV NAVELBINE, approximately one third were 65 years of age or greater. No overall differences in effectiveness or safety were observed between these patients and younger adult patients. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics of vinorelbine in elderly and younger adult patients are similar (see CLINICAL PHARMACOLOGY).

Adverse Reactions

The pattern of adverse reactions is similar whether NAVELBINE is used as a single agent or in combination. Adverse reactions from studies with single-agent and combination use of NAVELBINE are summarized in Tables 2-4.

Single-Agent NAVELBINE

Data in the following table are based on the experience of 365 patients (143 patients with NSCLC; 222 patients with advanced breast cancer) treated with IV NAVELBINE as a single agent in 3 clinical studies. The dosing schedule in each study was 30 mg/m2NAVELBINE on a weekly basis.

Table 2: Summary of Adverse Events in 365 Patients Receiving Single-Agent NAVELBINE*†:

Adverse Event			All Patients (n=365)	NSCLC (n=143)
Bone Marrow
Granulocytopenia	<2,000 cells/mm3		90%	80%
	<500 cells/mm3		36%	29%
Leukopenia	<4,000 celIs/mm3		92%	81%
	<1,000 cells/mm3		15%	12%
Thrombocytopenia	<100,000 cells/mm3		5%	4%
	<50,000 cells/mm3		1%	1%
Anemia	<11 g/dL		83%	77%
	<8 g/dL		9%	1%
Hospitalizations due to granulocytopenic complications			9%	8%

Table 2: Summary of Adverse Events in 365 Patients Receiving Single-Agent NAVELBINE*†:

* None of the reported toxicities were influenced by age. Grade based on modified criteria from the National Cancer Institute. † Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy. ‡ Incidence of paresthesia plus hypesthesia.
	All Grades		Grade 3		Grade 4
	All Patients	NSCLC	All Patients	NSCLC	All Patients	NSCLC
Clinical Chemistry
Elevations
Total Bilirubin (n=351)	13%	9%	4%	3%	3%	2%
SGOT (n=346)	67%	54%	5%	2%	1%	1%
General
Asthenia	36%	27%	7%	5%	0%	0%
Injection Site Reactions	28%	38%	2%	5%	0%	0%
Injection Site Pain	16%	13%	2%	1%	0%	0%
Phlebitis	7%	10%	<1%	1%	0%	0%
Digestive
Nausea	44%	34%	2%	1%	0%	0%
Vomiting	20%	15%	2%	1%	0%	0%
Constipation	35%	29%	3%	2%	0%	0%
Diarrhea	17%	13%	1%	1%	0%	0%
Peripheral Neuropathy‡	25%	20%	1%	1%	<1%	0%
Dyspnea	7%	3%	2%	2%	1%	0%
Alopecia	12%	12%	<1%	1%	0%	0%

Hematologic

Granulocytopenia is the major dose-limiting toxicity with NAVELBINE. Dose adjustments are required for hematologic toxicity and hepatic insufficiency (see DOSAGE AND ADMINISTRATION). Granulocytopenia was generally reversible and not cumulative over time. Granulocyte nadirs occurred 7 to 10 days after the dose, with granulocyte recovery usually within the following 7 to 14 days. Granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of patients. Septic deaths occurred in approximately 1% of patients. Prophylactic hematologic growth factors have not been routinely used with NAVELBINE.

If medically necessary, growth factors may be administered at recommended doses no earlier than 24 hours after the administration of cytotoxic chemotherapy. Growth factors should not be administered in the period 24 hours before the administration of chemotherapy. Whole blood and/or packed red blood cells were administered to 18% of patients who received NAVELBINE.

Neurologic

Loss of deep tendon reflexes occurred in less than 5% of patients. The development of severe peripheral neuropathy was infrequent (1%) and generally reversible.

Skin

Like other antirancer vinca alkaloids, NAVELBINE is a moderate vesicant. Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Chemical phlebitis along the vein proximal to the site of injection was reported in 10% of patients.

Gastrointestinal

Prophylactic administration of antiemetics was not routine in patients treated with single-agent NAVELBINE. Due to the low incidence of severe nausea and vomiting with single-agent NAVELBINE, the use of serotonin antagonists is generally not required.

Hepatic

Transient elevations of liver enzymes were reported without clinical symptoms.

Cardiovascular

Chest pain was reported in 5% of patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction.

Pulmonary

Shortness of breath was reported in 3% of patients; it was severe in 2% (see WARNINGS). Interstitial pulmonary changes were documented.

Other

Fatigue occurred in 27% of patients. It was usually mild or moderate but tended to increase with cumulative dosing.

Other toxicities that have been reported in less than 5% of patients include jaw pain, myalgia, arthralgia, and rash. Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients.

Combination Use

Adverse events for combination use are summarized in Tables 3 and 4.

NAVELBINE in Combination with Cisplatin

NAVELBINE plus Cisplatin versus Single-Agent Cisplatin (Table 3): Myelosuppression was the predominant toxicity in patients receiving combination therapy, Grade 3 and 4 granulocytopenia of 82% compared to 5% in the single-agent cisplatin arm. Fever and/or sepsis related to granulocytopenia occurred in 11% of patients on NAVELBINE and cisplatin compared to 0% on the cisplatin arm. Four patients on the combination died of granulocytopenia-related sepsis. During this study, the use of granulocyte colony-stimulating factor ([G-CSF] filgrastim) was permitted, but not mandated, after the first course of treatment for patients who experienced Grade 3 or 4 granulocytopenia (x1,000 cells/mm3) or in those who developed neutropenic fever between cycles of chemotherapy. Beginning 24 hours after completion of chemotherapy, G-CSF was started at a dose of 5 mcg/kg per day and continued until the total granulocyte count was >1,000 cells/mm3 on 2 successive determinations. G-CSF was not administered on the day of treatment. Grade 3 and 4 anemia occurred more frequently in the combination arm compared to control, 24% vs. 8%, respectively. Thrombocytopenia occurred in 6% of patients treated with NAVELBINE plus cisplatin compared to 2% of patients treated with cisplatin. The incidence of severe non-hematologic toxicity was similar among the patients in both treatment groups. Patients receiving NAVELBINE plus cisplatin compared to single-agent cisplatin experienced more Grade 3 and/or 4 peripheral numbness (2% vs. <1%), phlebitis/thrombosis/embolism (3% vs. <1%), and infection (6% vs. <1%). Grade 3-4 constipation and/or ileus occurred in 3% of patients treated with combination therapy and in 1% of patients treated with cisplatin. Seven deaths were reported on the combination arm; 2 were related to cardiac ischemia, 1 massive cerebrovascular accident, 1 multisystem failure due to an overdose of NAVELBINE, and 3 from febrile neutropenia. One death, secondary to respiratory infection unrelated to granulocytopenia, occurred with single-agent cisplatin.

NAVELBINE plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine (Table 4)

Myelosuppression, specifically Grade 3 and 4 granulocytopenia, was significantly greater with the combination of NAVELBINE plus cisplatin (79%) than with either single-agent NAVELBINE (53%) or vindesine plus cisplatin (48%), P<0.0001. Hospitalization due to documented sepsis occurred in 4.4% of patients treated with NAVELBINE plus cisplatin: 2% of patients treated with vindesine and cisplatin, and 4% of patients treated with single-agent NAVELBINE. Grade 3 and 4 thrombocytopenia was infrequent in patients receiving combination chemotherapy and no events were reported with single-agent NAVELBINE.

The incidence of Grade 3 and/or 4 nausea and vomiting, alopecia, and renal toxicity were reported more frequently in the cisplatin-containing combinations compared to single-agent NAVELBINE. Severe localNAVELBINE® (vinorelbine tartrate) Injection reactions occurred in 2% of patients treated with combinations containing NAVELBINE; none were observed in the vindesine plus cisplatin arm. Grade 3 and 4 neurotoxicity was significantly more frequent in patients receiving vindesine plus cisplatin (17%) comparedto NAVELBINE plus cisplatin (7%) and single-agent vinorelbine (9%) (P<0.005). Cisplatin did not appear to increase the incidence of neurotoxicity observed with single-agent NAVELBINE.

Table 3: Selected Adverse Events From a Comparative Trial of NAVELBINE plus Cisplatin versus Single-Agent Cisplatin*

*Graded according to the standard SWOG criteria.
	NAVELBINE 25 mg/m2 plus Cisplatin 100 mg/m2 (n=212)			Cisplatin 100 mg/m2 (n=210)
Adverse Event	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Bone Marrow
Granulocytopenia	89%	22%	60%	26%	4%	1%
Anemia	88%	21%	3%	72%	7%	<1%
Leukopenia	88%	39%	19%	31%	<1%	0%
Thrombocytopenia	29%	4%	1%	21%	1%	<1%
Febrile neutropenia	N/A	N/A	11%	N/A	N/A	0%
Hepatic
Elevated transaminase	1%	0%	0%	<1%	<1%	0%
Renal
Elevated creatinine	37%	2%	2%	28%	4%	<1%
Non-Laboratory
Malaise/fatigue/lethargy	67%	12%	0%	49%	8%	0%
Vomiting	60%	7%	6%	60%	10%	4%
Nausea	58%	14%	0%	57%	12%	0%
Anorexia	46%	0%	0%	37%	0%	0%
Constipation	35%	3%	0%	16%	1%	0%
Alopecia	34%	0%	0%	14%	0%	0%
Weight loss	34%	1%	0%	21%	<1%	0%
Fever without infection	20%	2%	0%	4%	0%	0%
Hearing	18%	4%	0%	18%	3%	<1%
Local (injection site reactions)	17%	<1%	0%	1%	0%	0%
Diarrhea	17%

Acyclovir Injection

Dosage Form: injection, powder, for solution
Acyclovir Sodium Injection

FOR INTRAVENOUS INFUSION ONLY

Acyclovir Injection Description

Acyclovir Sodium Injection is a synthetic nucleoside analog, active against herpes viruses.  It is a sterile, aqueous solution for intravenous infusion, containing 50 mg acyclovir per mL in Water for Injection, USP.  The concentration is equivalent to 54.9 mg of acyclovir sodium per mL in Water for Injection, USP.  The sodium content is approximately 5.1 mg/mL.  The pH range of the solution is 10.85 to 11.50.  Further dilution of Acyclovir Sodium Injection in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION, Administration).

The chemical name of acyclovir sodium is 9-[(2-Hydroxyethoxy)methyl] guanine, and has the following structural formula:

 

 

Acyclovir sodium is a white, crystalline powder with the molecular formula C8H10N5NaO3 and a molecular weight of 247.19.  The maximum solubility in water at 25°C exceeds 100 mg/mL.  At physiologic pH, acyclovir sodium exists as the unionized form with a molecular weight of 225 and a maximum solubility in water at 37°C of 2.5 mg/mL.  The pka’s of acyclovir are 2.27 and 9.25.

VIROLOGY

Mechanism of Antiviral Action

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2) and varicella-zoster virus (VZV).

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV.  This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue.  The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes.  In vitro, acyclovir triphosphate stops replication of herpes viral DNA.  This is accomplished in three ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase.  The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities

The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized.  Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors.  Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2.  The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL.  Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.

Drug Resistance

Resistance of HSV and VZV to acyclovir can result from qualitative or quantitative changes in the viral TK and/or DNA polymerase.  Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection.  While most of the acyclovir-resistant mutants isolated thus far from such patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated.  TK-negative mutants may cause severe disease in infants and immunocompromised adults.  The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

Acyclovir Injection - Clinical Pharmacology

Pharmacokinetics

The pharmacokinetics of acyclovir after intravenous administration have been evaluated in adult patients with normal renal function during Phase 1/2 studies after single doses ranging from 0.5 to 15 mg/kg and after multiple doses ranging from 2.5 to 15 mg/kg every 8 hours.  Proportionality between dose and plasma levels is seen after single doses or at steady-state after multiple dosing.  Average steady-state peak and trough concentrations from 1-hour infusions administered every 8 hours are given in Table 1.

Table 1: Acyclovir Peak and Trough Concentrations

                          at Steady-State

Dosage Regimen	CSSmax	CSStrough
5 mg/kg q 8 h (n=8)	9.8 mcg/mL range: 5.5 to 13.8	0.7 mcg/mL range: 0.2 to 1
10 mg/kg q 8 h (n=7)	22.9 mcg/mL range: 14.1 to 44.1	1.9 mcg/mL range: 0.5 to 2.9

Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values.  Plasma protein binding is relatively low (9% to 33%) and drug interactions involving binding site displacement are not anticipated.

Renal excretion of unchanged drug is the major route of acyclovir elimination accounting for 62% to 91% of the dose.  The only major urinary metabolite detected is 9-carboxymethoxymethylguanine accounting for up to 14.1% of the dose in patients with normal renal function.

The half-life and total body clearance of acyclovir are dependent on renal function as shown in Table 2.

 

      Table 2: Acyclovir Half-life and Total Body Clearance

Creatinine Clearance (mL/min/1.73 m2)		Total Body Clearance
	Half-Life (hr)	(mL/min/1.73 m2)	(mL/min/kg)
>80 50-80 15-50 0 (Anuric)	2.5 3 3.5 19.5	327 248 190 29	5.1 3.9 3.4 0.5

Special Populations

Adults With Impaired Renal Function

Acyclovir was administered at a dose of 2.5 mg/kg to 6 adult patients with severe renal failure.  The peak and trough plasma levels during the 47 hours preceding hemodialysis were 8.5 mcg/mL and 0.7 mcg/mL, respectively.

Consult DOSAGE AND ADMINISTRATION section for recommended adjustments in dosing based upon creatinine clearance.

 

Pediatrics

Acyclovir pharmacokinetics were determined in 16 pediatric patients with normal renal function ranging in age from 3 months to 16 years at doses of approximately 10 mg/kg and 20 mg/kg every 8 hours (Table 3).  Concentrations achieved at these regimens are similar to those in adults receiving 5 mg/kg and 10 mg/kg every 8 hours, respectively (Table 1).  Acyclovir pharmacokinetics were determined in 12 patients ranging in age from birth to 3 months at doses of 5 mg/kg, 10 mg/kg, and 15 mg/kg every 8 hours (Table 3).

 

        Table 3: Acyclovir Pharmacokinetics in Pediatric Patients (Mean ± SD)

Parameter	Birth to 3 Months of Age (n=12)	3 Months to 12 Years of Age (n=16)
CL (mL/min/kg)	4.46 ± 1.61	8.44 ± 2.92
VDSS (L/kg)	1.08 ± 0.35	1.01 ± 0.28
Elimination half-life (hours)	3.80 ± 1.19	2.36 ± 0.97

Geriatrics

Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function.  Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use).

Drug Interactions

Coadministration of probenecid with acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve.  Urinary excretion and renal clearance were correspondingly reduced.

CLINICAL TRIALS

Herpes Siplex Infections in Immuocompromised Patients

A multicenter trial of acyclovir at a dose of 250 mg/m2 every 8 hours (750 mg/m2/day) for 7 days was conducted in 98 immunocompromised patients (73 adults and 25 children) with orofacial, esophageal, genital and other localized infections (52 treated with acyclovir and 46 with placebo).  Acyclovir decreased virus excretion, reduced pain, and promoted healing of lesions.

Initial Episodes of Herpes Genitalis

In placebo-controlled trials, 58 patients with initial genital herpes were treated with intravenous acyclovir 5 mg/kg or placebo (27 patients treated with acyclovir and 31 treated with placebo) every 8 hours for 5 days.  Acyclovir decreased the duration of viral excretion, new lesion formation, and duration of vesicles, and promoted healing of lesions.

Herpes Simplex Encephalitis

Sixty-two patients ages 6 months to 79 years with brain biopsy-proven herpes simplex encephalitis were randomized to receive either acyclovir (10 mg/kg every 8 hours) or vidarabine (15 mg/kg/day) for 10 days (28 were treated with acyclovir and 34 with vidarabine).  Overall mortality at 12 months for patients treated with acyclovir was 25% compared to 59% for patients treated with vidarabine.  The proportion of patients treated with acyclovir functioning normally or with only mild sequelae (e.g., decreased attention span) was 32% compared to 12% of patients treated with vidarabine.

Patients less than 30 years of age and those who had the least severe neurologic involvement at time of entry into study had the best outcome with treatment with acyclovir.  An additional controlled study performed in Europe demonstrated similar findings.

Neonatal Herpes Simplex Virus Infection

Two hundred and two infants with neonatal herpes simplex infections were randomized to receive either acyclovir 10 mg/kg every 8 hours (n=107) or vidarabine 30 mg/kg/day (n=95) for 10 days.  Outcomes are presented in Table 4.

 

               Table 4: Mortality at 1 Year

HSV Disease Classification	Treatment Group
	Acyclovir (n=107)	Vidarabine (n=95)
SEM* (n=85)	0/54	0/31
CNS† (n=71)	5/35	5/36
DISS‡ (n=46)	11/18	14/28

* SEM refers to localized infection with disease limited to skin, eye, and/or mouth.

† CNS refers to infection of the central nervous system with compatible neurologic and CSF findings.

‡ DISS refers to visceral organ involvement such as hepatitis or pneumonitis with or without CNS involvement.

 

Rates of neurologic sequelae at 1 year were comparable between the treatment groups.

Varicella-Zoster Infetions in Immunocompromised Patients

A multicenter trial of acyclovir at a dose of 500 mg/m2 every 8 hours for 7 days was conducted in immunocompromised patients with zoster infections (shingles).  Ninety-four (94) patients were evaluated (52 patients were treated with acyclovir and 42 with placebo).  Acyclovir was superior to placebo as measured by reductions in cutaneous dissemination and visceral dissemination.

Indications and Usage for Acyclovir Injection

Herpes Simplex Infections in Immunocompromised Patients

Acyclovir Sodium Injection is indicated for the treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients.

Initial Episodes of Herpes Genitalis

Acyclovir Sodium Injection is indicated for the treatment of severe initial clinical episodes of herpes genitalis in immuno-competent patients.

Herpes Simplex Encephalitis

Acyclovir Sodium Injection is indicated for the treatment of herpes simplex encephalitis.

Neonatal Herpes Simplex Virus Infection

Acyclovir Sodium Injection is indicated for the treatment of neonatal herpes infections.

Varicella-Zoster Infections in Immunocompromised Patients

Acyclovir Sodium Injection is indicated for the treatment of varicella-zoster (shingles) infections in immunocompromised patients.

Contraindications

Acyclovir Sodium Injection is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.

Warnings

Acyclovir Sodium Injection is intended for intravenous infusion only, and should not be administered topically, intramuscularly, orally, subcutaneously, or in the eye.  Intravenous infusions must be given over a period of at least 1 hour to reduce the risk of renal tubular damage (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE).  Thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.

Precautions

General

Precipitation of acyclovir crystals in renal tubules can occur if the maximum solubility of free acyclovir (2.5 mg/mL at 37°C in water) is exceeded or if the drug is administered by bolus injection.  Ensuing renal tubular damage can produce acute renal failure.

Abnormal renal function (decreased creatinine clearance) can occur as a result of acyclovir administration and depends on the state of the patient’s hydration, other treatments, and the rate of drug administration.  Concomitant use of other nephrotoxic drugs, pre-existing renal disease, and dehydration make further renal impairment with acyclovir more likely.

Administration of acyclovir by intravenous infusion must be accompanied by adequate hydration.

When dosage adjustments are required, they should be based on estimated creatinine clearance (see DOSAGE AND ADMINISTRATION).

Approximately 1% of patients receiving intravenous acyclovir have manifested encephalopathic changes characterized by either lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures, or coma.  Acyclovir should be used with caution in those patients who have underlying neurologic abnormalities and those with serious renal, hepatic, or electrolyte abnormalities, or significant hypoxia.

Drug Interactions

See CLINICAL PHARMACOLOGY: Pharmacokinetics.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 30 mg/kg/day (10 mg/kg every 8 hours, dosing appropriate for treatment of herpes zoster or herpes encephalitis), or 15 mg/kg/day (5 mg/kg every 8 hours, dosing appropriate for treatment of primary genital herpes or herpes simplex infections in immunocompromised patients).  Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage.  There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors.  At 450 mg/kg/day, plasma concentrations in both the mouse and rat bioassay were lower than concentrations in humans.

Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays.  Acyclovir was positive in 5 of the assays.

Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, PO) or in rats (25 mg/kg/day, SC).  In the mouse study, plasma levels were the same as human levels, while in the rat study, they were 1 to 2 times human levels.  At higher doses (50 mg/kg/day, SC) in rats and rabbits (1 to 2 and 1 to 3 times human levels, respectively) implantation efficacy, but not litter size, was decreased.  In a rat peri- and post-natal study at 50 mg/kg/day, SC, there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses.

No testicular abnormalities were seen in dogs given 50 mg/kg/day, IV for 1 month (1 to 3 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (the same as human levels).  Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.

Pregnancy: Teratogenic Effects

Pregnancy Category B.

Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg/day, PO), rabbit (50 mg/kg/day, SC and IV) or rat (50 mg/kg/day, SC).  These exposures resulted in plasma levels the same as, 4 and 9, and 1 and 2 times, respectively, human levels.

There are no adequate and well-controlled studies in pregnant women.  A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999.  There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes.  The occurrence rate of birth defects approximates that found in the general population.  However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.  Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Acyclovir concentrations have been documented in breast milk in two women following oral administration of acyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels.  These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day.  Acyclovir should be administered to a nursing mother with caution and only when indicated.

Pediatric Use

See DOSAGE AND ADMINISTRATION.

Geriatric Use

Clinical studies of acyclovir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.  Other reported clinical experience has identified differences in the severity of CNS adverse events between elderly and younger patients (see ADVERSE REACTIONS: Observed During Clinical Practice).  In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, and of concomitant disease or other drug therapy.  This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.  Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

The adverse reactions listed below have been observed in controlled and uncontrolled clinical trials in approximately 700 patients who received acyclovir at approximately 5 mg/kg (250 mg/m2) 3 times daily, and approximately 300 patients who received approximately 10 mg/kg (500 mg/m2) 3 times daily.

The most frequent adverse reactions reported during administration of acyclovir were inflammation or phlebitis at the injection site in approximately 9% of the patients, and transient elevations of serum creatinine or BUN in 5% to 10% (the higher incidence occurred usually following rapid [less than 10 minutes] intravenous infusion).  Nausea and/or vomiting occurred in approximately 7% of the patients (the majority occurring in nonhospitalized patients who received 10 mg/kg).  Itching, rash, or hives occurred in approximately 2% of patients.  Elevation of transaminases occurred in 1% to 2% of patients.

The following hematologic abnormalities occurred at a frequency of less than 1%: anemia, neutropenia, thrombocytopenia, thrombocytosis, leukocytosis, and neutrophilia.  In addition, anorexia and hematuria were observed.

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of Acyclovir Sodium Injection in clinical practice.  Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.  These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to acyclovir, or a combination of these factors.

General:  Anaphylaxis, angioedema, fatigue, fever, headache, pain, peripheral edema.

Digestive:  Abdominal pain, diarrhea, gastrointestinal distress, nausea.

Cardiovascular:  Hypotension.

Hematologic and Lymphatic:  Disseminated intravascular coagulation, hemolysis,leukocytoclastic vasculitis, leukopenia, lymphadenopathy.

Hepatobiliary Tract and Pancreas:  Elevated liver function tests, hepatitis, hyperbilirubinemia,jaundice.

Musculoskeletal:  Myalgia.

Nervous:  Aggressive behavior, agitation, ataxia, coma, confusion, delirium, dizziness, dysathria, encephalopathy, hallucinations, obtundation, paresthesia, psychosis, seizure, somnolence, tremor.  These symptoms may be marked, particularly in older adults (see PRECAUTIONS).

Skin:  Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.  Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion of acyclovir into extravascular tissues.

Special Senses:  Visual abnormalities.

Urogenital:  Renal failure, elevated blood urea nitrogen, elevated creatinine (see WARNINGS).

Overdosage

Overdoses involving ingestions of up to 20 g have been reported.  Adverse events that have been reported in association with overdosage include agitation, coma, seizures, and lethargy.  Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid.  Overdosage has been reported following bolus injections or inappropriately high doses, and in patients whose fluid and electrolyte balance were not properly monitored.  This has resulted in elevated BUN and serum creatinine, and subsequent renal failure.  In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION).

Acyclovir Injection Dosage and Administration

CAUTION - RAPID OR BOLUS INTRAVENOUS INJECTION MUST BE AVOIDED (see WARNINGS and PRECAUTIONS).

INTRAMUSCULAR OR SUBCUTANEOUS INJECTION MUST BE AVOIDED (see WARNINGS).

Therapy should be initiated as early as possible following onset of signs and symptoms of herpes infections. 

A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.

Dosage

HERPES SIMPLEX INFECTIONS

MUCOSAL AND CUTANEOUS HERPES SIMPLEX (HSV-1 and HSV-2)

INFECTIONS IN IMMUNOCOMPROMISED PATIENTS:

Adults and Adolescents (12 years of age and older):

5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

 

Pediatrics (Under 12 years of age):

10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

 

SEVERE INITIAL CLINICAL EPISODES OF HERPES GENITALIS:

Adults and Adolescents (12 years of age and older):

5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

 

HERPES SIMPLEX ENCEPHALITIS:

Adults and Adolescents (12 years of age and older): 

10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

 

Pediatrics (3 months to 12 years of age):

20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

 

Neonatal Herpes Simplex Virus Infections (Birth to 3 months):

10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.  In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

VARICELLA-ZOSTER INFECTIONS

ZOSTER IN IMMUNO­COMPROMISED PATIENTS:

Adults and Adolescents (12 years of age and older: 

10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

 

Pediatrics (Under 12 years of age):

20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

Obese Patients

Obese patients should be dosed at the recommended adult dose using Ideal Body Weight.

PATIENTS WITH ACUTE OR CHRONIC RENAL IMPAIRMENT: Refer to DOSAGE AND ADMINISTRATION section for recommended doses, and adjust the dosing interval as indicated in Table 5.

Table 5: Dosage Adjustments for Patients with Renal Impairment

Creatinine Clearance (mL/min/1.73 m2)	Percent of Recommended Dose	Dosing Interval (hours)
>50 25-50 10-25 0-10	100% 100% 100% 50%	8 12 24 24

Hemodialysis

For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours.  This results in a 60% decrease in plasma concentrations following a six-hour dialysis period.  Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

Peritoneal Dialysis

No supplemental dose appears to be necessary after adjustment of the dosing interval.

Administration

The calculated dose should be further diluted in an appropriate intravenous solution at a volume selected for administration during each 1 hour infusion.  Infusion concentrations of approximately 7 mg/mL or lower are recommended.  In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose.  Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation.  Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended.

Once diluted for administration, each dose should be used within 24 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How is Acyclovir Injection Supplied

Acyclovir Sodium Injection is available as:

Product No.	NDC No.
302510	63323-325-10	Acyclovir Sodium Injection equivalent to acyclovir, 50 mg/mL in a 10 mL plastic vial, in packages of 10.
302520	63323-325-20	Acyclovir Sodium Injection equivalent to acyclovir, 50 mg/mL in a 20 mL plastic vial, in packages of 10.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Discard unused portion.

Vial stoppers do not contain natural rubber latex.

45769G

Revised: March 2008

PACKAGE LABEL - PRINCIPAL DISPLAY - Acyclovir 10 mL Single Dose Vial Label

NDC 63323-325-10

302510

Acyclovir Sodium Injection

500 mg/10 mL*

(50 mg/mL)

For IV Infusion Only

Must Be Diluted Prior To Use

Rx only

10 mL Single Dose Vial

 

PACKAGE LABEL - PRINCIPAL DISPLAY - Acyclovir 10 mL Single Dose Vial Tray Label

NDC 63323-325-10

302510

Acyclovir Sodium Injection

500 mg/10 mL*

(50 mg/mL)

For IV Infusion Only

Must Be Diluted Prior To Use

10 mL Single Dose Vial

10 Vials

Rx only

 

ACYCLOVIR  acyclovir sodium  injection, powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63323-325 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ACYCLOVIR SODIUM (ACYCLOVIR) ACYCLOVIR 50 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63323-325-10 10 VIAL In 1 TRAY contains a VIAL, SINGLE-DOSE 1 10 mL In 1 VIAL, SINGLE-DOSE This package is contained within the TRAY (63323-325-10) 2 63323-325-20 10 VIAL In 1 TRAY contains a VIAL, SINGLE-DOSE 2 20 mL In 1 VIAL, SINGLE-DOSE This package is contained within the TRAY (63323-325-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA074930	10/17/2000

Labeler - APP Pharmaceuticals, LLC (608775388)

Establishment
Name	Address	ID/FEI	Operations
APP Pharmaceuticals, LLC		840771732	MANUFACTURE

Revised: 01/2012APP Pharmaceuticals, LLC