Anastrozole
ANASTROZOLE — anastrozole tablet, film coated
A-S Medication Solutions
1 INDICATIONS AND USAGE
1.1 Adjuvant Treatment
Anastrozole tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
1.2 First-Line Treatment
Anastrozole tablets are indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer.
1.3 Second-Line Treatment
Anastrozole tablets are indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to anastrozole tablets.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The dose of anastrozole is one 1 mg tablet taken once a day. For patients with advanced breast cancer, anastrozole tablets should be continued until tumor progression. Anastrozole tablets can be taken with or without food.
For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, anastrozole tablets were administered for five years [see Clinical Studies (14.1)].
No dosage adjustment is necessary for patients with renal impairment or for elderly patients [see Use in Specific Populations (8.6)].
2.2 Patients with Hepatic Impairment
No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole tablets have not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].
3 DOSAGE FORMS AND STRENGTHS
The tablets are white, biconvex, film-coated containing 1 mg of anastrozole. The tablets are debossed with ‘A1’ on one side and plain on the other side.
4 CONTRAINDICATIONS
Hypersensitivity Anastrozole tablets are contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
5.1 Ischemic Cardiovascular Events
In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with anastrozole in the ATAC trial (17% of patients on anastrozole and 10% of patients on tamoxifen). Consider risk and benefits of anastrozole therapy in patients with pre-existing ischemic heart disease [see Adverse Reactions (6.1)].
5.2 Bone Effects
Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Consider bone mineral density monitoring in patients treated with anastrozole [see Adverse Reactions (6.1)].
5.3 Cholesterol
During the ATAC trial, more patients receiving anastrozole were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively) [see Adverse Reactions (6.1)].
5.4 Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, anastrozole can cause fetal harm when administered to a pregnant woman. Anastrozole caused embryo-fetal toxicities in rats at maternal exposure that were 9 times the human clinical exposure, based on area under the curve (AUC). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m2 basis. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with anastrozole and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
6 ADVERSE REACTIONS
Serious adverse reactions with anastrozole occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling [see Adverse Reactions (6.2)].
Common adverse reactions (occurring with an incidence of ≥10%) in women taking anastrozole included: hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema.
In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as a result of hot flashes in the anastrozole group.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
6.1 Clinical Trials Experience
Adjuvant Therapy
Adverse reaction data for adjuvant therapy are based on the ATAC trial [see Clinical Studies (14.1)]. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and tamoxifen 20 mg, respectively.
Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1.
| Body system and adverse reactions by COSTART † preferred term ‡ | Anastrozole 1 mg (N § =3092) | Tamoxifen 20 mg (N § =3094) |
|---|---|---|
| * The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.† COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms.‡ A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system.§ N=Number of patients receiving the treatment.¶ Vaginal Hemorrhage without further diagnosis. | ||
| Body as a whole | ||
| Asthenia | 575 (19) | 544 (18) |
| Pain | 533 (17) | 485 (16) |
| Back pain | 321 (10) | 309 (10) |
| Headache | 314 (10) | 249 (8) |
| Abdominal pain | 271 (9) | 276 (9) |
| Infection | 285 (9) | 276 (9) |
| Accidental injury | 311 (10) | 303 (10) |
| Flu syndrome | 175 (6) | 195 (6) |
| Chest pain | 200 (7) | 150 (5) |
| Neoplasm | 162 (5) | 144 (5) |
| Cyst | 138 (5) | 162 (5) |
| Cardiovascular | ||
| Vasodilatation | 1104 (36) | 1264 (41) |
| Hypertension | 402 (13) | 349 (11) |
| Digestive | ||
| Nausea | 343 (11) | 335 (11) |
| Constipation | 249 (8) | 252 (8) |
| Diarrhea | 265 (9) | 216 (7) |
| Dyspepsia | 206 (7) | 169 (6) |
| Gastrointestinal disorder | 210 (7) | 158 (5) |
| Hemic and lymphatic | ||
| Lymphedema | 304 (10) | 341 (11) |
| Anemia | 113 (4) | 159 (5) |
| Metabolic and nutritional | ||
| Peripheral edema | 311 (10) | 343 (11) |
| Weight gain | 285 (9) | 274 (9) |
| Hypercholesterolemia | 278 (9) | 108 (3.5) |
| Musculoskeletal | ||
| Arthritis | 512 (17) | 445 (14) |
| Arthralgia | 467 (15) | 344 (11) |
| Osteoporosis | 325 (11) | 226 (7) |
| Fracture | 315 (10) | 209 (7) |
| Bone pain | 201 (7) | 185 (6) |
| Arthrosis | 207 (7) | 156 (5) |
| Joint Disorder | 184 (6) | 160 (5) |
| Myalgia | 179 (6) | 160 (5) |
| Nervous system | ||
| Depression | 413 (13) | 382 (12) |
| Insomnia | 309 (10) | 281 (9) |
| Dizziness | 236 (8) | 234 (8) |
| Anxiety | 195 (6) | 180 (6) |
| Paresthesia | 215 (7) | 145 (5) |
| Respiratory | ||
| Pharyngitis | 443 (14) | 422 (14) |
| Cough increased | 261 (8) | 287 (9) |
| Dyspnea | 234 (8) | 237 (8) |
| Sinusitis | 184 (6) | 159 (5) |
| Bronchitis | 167 (5) | 153 (5) |
| Skin and appendages | ||
| Rash | 333 (11) | 387 (13) |
| Sweating | 145 (5) | 177 (6) |
| Special Senses | ||
| Cataract Specified | 182 (6) | 213 (7) |
| Urogenital | ||
| Leukorrhea | 86 (3) | 286 (9) |
| Urinary tract infection | 244 (8) | 313 (10) |
| Breast pain | 251 (8) | 169 (6) |
| Breast Neoplasm | 164 (5) | 139 (5) |
| Vulvovaginitis | 194 (6) | 150 (5) |
| Vaginal Hemorrhage¶ | 122 (4) | 180 (6) |
| Vaginitis | 125 (4) | 158 (5) |
Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see Table 2).
| * Patients with multiple events in the same category are counted only once in that category.† Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia.‡ Percentages calculated based upon the numbers of patients with an intact uterus at baseline. | ||||
| Anastrozole N=3092 (%) | Tamoxifen N=3094 (%) | Odds-ratio | 95% CI | |
| Hot Flashes | 1104 (36) | 1264 (41) | 0.80 | 0.73 to 0.89 |
| Musculoskeletal Events† | 1100 (36) | 911 (29) | 1.32 | 1.19 to 1.47 |
| Fatigue/Asthenia | 575 (19) | 544 (18) | 1.07 | 0.94 to 1.22 |
| Mood Disturbances | 597 (19) | 554 (18) | 1.10 | 0.97 to 1.25 |
| Nausea and Vomiting | 393 (13) | 384 (12) | 1.03 | 0.88 to 1.19 |
| All Fractures | 315 (10) | 209 (7) | 1.57 | 1.30 to 1.88 |
| Fractures of Spine, Hip, or Wrist | 133 (4) | 91 (3) | 1.48 | 1.13 to 1.95 |
| Wrist/Colles’ fractures | 67 (2) | 50 (2) | ||
| Spine fractures | 43 (1) | 22 (1) | ||
| Hip fractures | 28 (1) | 26 (1) | ||
| Cataracts | 182 (6) | 213 (7) | 0.85 | 0.69 to 1.04 |
| Vaginal Bleeding | 167 (5) | 317 (10) | 0.50 | 0.41 to 0.61 |
| Ischemic Cardiovascular Disease | 127 (4) | 104 (3) | 1.23 | 0.95 to 1.60 |
| Vaginal Discharge | 109 (4) | 408 (13) | 0.24 | 0.19 to 0.30 |
| Venous Thromboembolic Events | 87 (3) | 140 (5) | 0.61 | 0.47 to 0.80 |
| Deep Venous Thromboembolic Events | 48 (2) | 74 (2) | 0.64 | 0.45 to 0.93 |
| Ischemic Cerebrovascular Event | 62 (2) | 88 (3) | 0.70 | 0.50 to 0.97 |
| Endometrial Cancer‡ | 4 (0.2) | 13 (0.6) | 0.31 | 0.10 to 0.94 |
Ischemic Cardiovascular Events
Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% anastrozole vs. 3% tamoxifen).
In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the anastrozole arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the anastrozole arm and 34/3094 (1.1%) patients in the tamoxifen arm.
In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on anastrozole and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving anastrozole and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving anastrozole and 8/249 (3.2%) patients receiving tamoxifen.
Bone Mineral Density Findings
Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.
Because anastrozole lowers circulating estrogen levels it may cause a reduction in bone mineral density.
A post-marketing trial assessed the combined effects of anastrozole and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates. Bisphosphonate treatment preserved bone density in most patients at risk of fracture.
Postmenopausal women with early breast cancer scheduled to be treated with anastrozole should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.
Cholesterol
During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).
A post-marketing trial also evaluated any potential effects of anastrozole on lipid profile. In the primary analysis population for lipids (anastrozole alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months.
In secondary population for lipids (anastrozole+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months.
In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline.
In this trial, treatment for 12 months with anastrozole alone had a neutral effect on lipid profile. Combination treatment with anastrozole and risedronate also had a neutral effect on lipid profile.
The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with anastrozole should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations.
Other Adverse Reactions
Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)].
Patients receiving anastrozole had a higher incidence of carpal tunnel syndrome [78 (2.5%)] compared with patients receiving tamoxifen [22 (0.7%)].
Vaginal bleeding occurred more frequently in the tamoxifen-treated patients versus the anastrozole-treated patients 317 (10%) versus 167 (5%), respectively.
Patients receiving anastrozole had a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen.
10-year median follow-up Safety Results from the ATAC Trial
Results are consistent with the previous analyses.
Serious adverse reactions were similar between anastrozole (50%) and tamoxifen (51%).
- Cardiovascular events were consistent with the known safety profiles of anastrozole and tamoxifen.
- The cumulative incidences of all first fractures (both serious and non-serious, occurring either during or after treatment) was higher in the anastrozole group (15%) compared to the tamoxifen group (11%). This increased first fracture rate during treatment did not continue in the post-treatment follow-up period.
- The cumulative incidence of new primary cancers was similar in the anastrozole group (13.7%) compared to the tamoxifen group (13.9%). Consistent with the previous analyses, endometrial cancer was higher in the tamoxifen group (0.8%) compared to the anastrozole group (0.2%).
- The overall number of deaths (during or off-trial treatment) was similar between the treatment groups. There were more deaths related to breast cancer in the tamoxifen than in the anastrozole treatment group.
First-Line Therapy
Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3.
| Body system Adverse Reaction* | Number (%) of subjects | |
|---|---|---|
| Anastrozole (N =506) | Tamoxifen (N =511) | |
| * A patient may have had more than 1 adverse event. | ||
| Whole body | ||
| Asthenia | 83 (16) | 81 (16) |
| Pain | 70 (14) | 73 (14) |
| Back pain | 60 (12) | 68 (13) |
| Headache | 47 (9) | 40 (8) |
| Abdominal pain | 40 (8) | 38 (7) |
| Chest pain | 37 (7) | 37 (7) |
| Flu syndrome | 35 (7) | 30 (6) |
| Pelvic pain | 23 (5) | 30 (6) |
| Cardiovascular | ||
| Vasodilation | 128 (25) | 106 (21) |
| Hypertension | 25 (5) | 36 (7) |
| Digestive | ||
| Nausea | 94 (19) | 106 (21) |
| Constipation | 47 (9) | 66 (13) |
| Diarrhea | 40 (8) | 33 (6) |
| Vomiting | 38 (8) | 36 (7) |
| Anorexia | 26 (5) | 46 (9) |
| Metabolic and Nutritional | ||
| Peripheral edema | 51 (10) | 41 (8) |
| Musculoskeletal | ||
| Bone pain | 54 (11) | 52 (10) |
| Nervous | ||
| Dizziness | 30 (6) | 22 (4) |
| Insomnia | 30 (6) | 38 (7) |
| Depression | 23 (5) | 32 (6) |
| Hypertonia | 16 (3) | 26 (5) |
| Respiratory | ||
| Cough increased | 55 (11) | 52 (10) |
| Dyspnea | 51 (10) | 47 (9) |
| Pharyngitis | 49 (10) | 68 (13) |
| Skin and appendages | ||
| Rash | 38 (8) | 34 (8) |
| Urogenital | ||
| Leukorrhea | 9 (2) | 31 (6) |
Less frequent adverse experiences reported in patients receiving anastrozole l mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy.
Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre-specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups.
| * A patient may have had more than 1 adverse reaction.† Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis.‡ Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct. | ||
| Number (n) and Percentage of Patients | ||
| Adverse Reaction* | Anastrozole 1 mg (N=506) n (%) | NOLVADEX 20 mg (N=511) n (%) |
| Depression | 23 (5) | 32 (6) |
| Tumor Flare | 15 (3) | 18 (4) |
| Thromboembolic Disease† | 18 (4) | 33 (6) |
| Venous† | 5 | 15 |
| Coronary and Cerebral‡ | 13 | 19 |
| Gastrointestinal Disturbance | 170 (34) | 196 (38) |
| Hot Flushes | 134 (26) | 118 (23) |
| Vaginal Dryness | 9 (2) | 3 (1) |
| Lethargy | 6 (1) | 15 (3) |
| Vaginal Bleeding | 5 (1) | 11 (2) |
| Weight Gain | 11 (2) | 8 (2) |
Second-Line Therapy
Anastrozole was tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the anastrozole-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction.
The principal adverse reaction more common with anastrozole than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below:
| * A patient may have had more than one adverse reaction. | ||||||
| Adverse Reaction* | Anastrozole 1 mg (N=262) | Anastrozole 10 mg (N=246) | Megestrol Acetate 160 mg (N=253) | |||
| n | % | n | % | n | % | |
| Asthenia | 42 | (16) | 33 | (13) | 47 | (19) |
| Nausea | 41 | (16) | 48 | (20) | 28 | (11) |
| Headache | 34 | (13) | 44 | (18) | 24 | (9) |
| Hot Flashes | 32 | (12) | 29 | (11) | 21 | (8) |
| Pain | 28 | (11) | 38 | (15) | 29 | (11) |
| Back Pain | 28 | (11) | 26 | (11) | 19 | (8) |
| Dyspnea | 24 | (9) | 27 | (11) | 53 | (21) |
| Vomiting | 24 | (9) | 26 | (11) | 16 | (6) |
| Cough Increased | 22 | (8) | 18 | (7) | 19 | (8) |
| Diarrhea | 22 | (8) | 18 | (7) | 7 | (3) |
| Constipation | 18 | (7) | 18 | (7) | 21 | (8) |
| Abdominal Pain | 18 | (7) | 14 | (6) | 18 | (7) |
| Anorexia | 18 | (7) | 19 | (8) | 11 | (4) |
| Bone Pain | 17 | (6) | 26 | (12) | 19 | (8) |
| Pharyngitis | 16 | (6) | 23 | (9) | 15 | (6) |
| Dizziness | 16 | (6) | 12 | (5) | 15 | (6) |
| Rash | 15 | (6) | 15 | (6) | 19 | (8) |
| Dry Mouth | 15 | (6) | 11 | (4) | 13 | (5) |
| Peripheral Edema | 14 | (5) | 21 | (9) | 28 | (11) |
| Pelvic Pain | 14 | (5) | 17 | (7) | 13 | (5) |
| Depression | 14 | (5) | 6 | (2) | 5 | (2) |
| Chest Pain | 13 | (5) | 18 | (7) | 13 | (5) |
| Paresthesia | 12 | (5) | 15 | (6) | 9 | (4) |
| Vaginal Hemorrhage | 6 | (2) | 4 | (2) | 13 | (5) |
| Weight Gain | 4 | (2) | 9 | (4) | 30 | (12) |
| Sweating | 4 | (2) | 3 | (1) | 16 | (6) |
| Increased Appetite | 0 | (0) | 1 | (0) | 13 | (5) |
Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole l mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.
Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection
Cardiovascular: Hypertension; thrombophlebitis
Hepatic: Gamma GT increased; SGOT increased; SGPT increased
Hematologic: Anemia; leukopenia
Metabolic and Nutritiona l: Alkaline phosphatase increased; weight loss
Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving anastrozole. Increases in LDL cholesterol have been shown to contribute to these changes.
Musculoskeletal: Myalgia; arthralgia; pathological fracture
Nervous: Somnolence; confusion; insomnia; anxiety; nervousness
Respiratory: Sinusitis; bronchitis; rhinitis
Skin and Appendages: Hair thinning (alopecia); pruritus
Urogenital: Urinary tract infection; breast pain
The incidences of the following adverse reaction groups potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the table below.
| Adverse Reaction Group | Anastrozole 1 mg (N=262) | Anastrozole 10 mg (N=246) | Megestrol Acetate 160 mg (N=253) | |||
|---|---|---|---|---|---|---|
| n | (%) | n | (%) | n | (%) | |
| Gastrointestinal Disturbance | 77 | (29) | 81 | (33) | 54 | (21) |
| Hot Flushes | 33 | (13) | 29 | (12) | 35 | (14) |
| Edema | 19 | (7) | 28 | (11) | 35 | (14) |
| Thromboembolic Disease | 9 | (3) | 4 | (2) | 12 | (5) |
| Vaginal Dryness | 5 | (2) | 3 | (1) | 2 | (1) |
| Weight Gain | 4 | (2) | 10 | (4) | 30 | (12) |
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